May 2015 by McMahon Group

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Volume 42 • Number 5 • May 2015

JC Sentinel Event:

4 6

IT Can Save Lives Or Do Harm—It’s All in the Planning

Dean Jordan: Why we need another new pharmacy school. Stakeholders scuffle over safety of generic drug labeling.

CLINICAL

22 24

The skinny on pharmacist’s value in bariatrics. ISMP: Multiple IV line mix-ups can be deadly.

OPERATIONS & MGMT

34 38 41

Some hospitals score big on HCAHPS survey. Q&A: Kyle Skiermont makes the case for specialty pharmacy. Sanborn and Evans describe their path to the C-suite.

TECHNOLOGY

Profiles in Pharmacy: St. David’s embraces technology.

Kcentra for Urgent Warfarin Reversal: Practical Considerations for Implementation See insert after page 48.

ASHP May Urge Profession To Reject Business of Killing

lthough information technology (IT) systems can increase patient safety, poorly designed or implemented health IT can do the exact opposite, contributing to patient harm, according to a Sentinel Event Alert recently sent out by the Joint Commission. Medication mismanagement was listed as a frequent perpetrator of adverse events, according to the Joint Commission, which gave several examples: • A nurse entered a 3-year-old child’s weight into the electronic health record (EHR) as 32 kg, instead of 32 lb and the child was given a potentially lethal dose of medication. • A physician chose an inappropriate delivery route from a dropdown menu and a medication was ordered as an intramuscular injection, instead of IV.

•

ealth-system pharmacists may soon face an ethical dilemma on the issue of capital punishment: Should they oppose the profession taking an active role in the preparation of drugs for lethal injections or leave the decision up to the individual? In April, the American Society of Health-System Pharmacists took the first step to what could become a new, more restrictive policy on the issue, potentially bringing the ASHP into line with other health care organizations that oppose members’ participation in carrying out the death penalty.

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see SENTINEL EVENT, T page 42

A.S.P.E.N conference:

Pediatric Feeding Gap in ICU Hurts Hospitals, Patients Long Beach, Calif.—Malnutrition among critically ill children is a common and significant contributor to poor clinical outcomes and greater hospital costs, according to abstracts presented at the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) annual conference. To reverse that concerning trend, researchers presented novel tools to

•

see FEEDING GAP, P page 25

see KILLING DRUGS, page 18

State Laws Seek To Hamstring Pharmacists in Biosimilar Arena

harmacy trade associations and the FDA are not happy about state laws that they say will unnecessarily hamstring pharmacists’ ability to switch patients to biosimilar products poised for market entry. The restrictive legislation “will undermine trust in [biosimilars], are worrisome and represent a disservice to patients who could benefit from these lower cost treatments,” FDA spokesman Kristofer Baumgartner told Pharmacy Practice News. “[Given] the high standards for approval of biosimilar and interchangeable products,” he

FDA Approval Corlanor, the first new CHF drug approved in nearly a decade. See page 43

added, “patients and health care professionals can be assured that, when these products go to market, they will meet the [requirements for] safety, efficacy and high quality that everyone expects and counts on.” The first test case in this controversy is Sandoz’s filgrastim biosimilar Zarxio, the first biosimilar to be approved in the United States. As increasing numbers of states pass laws that restrict substitution, pharmacists will be unable to automatically switch Zarxio for Amgen’s Neupogen because the

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POLICY

see BIOSIMILARS, page 8

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Up Front 3

Pharmacy Practice News • May 2015

Capsules

Exercise Is Beneficial For Lung Cancer Patients

Web Exclusives Visit us online for Web-exclusive content. Links to all of the articles below can be found at pharmacypracticenews.com/ webex0515 or via your smart phone by scanning the adjacent 2D barcode. Be sure to check the Pharmacy Practice News site every day for late-breaking news!

t’s understandable for hematology/oncology pharmacists to focus on drug therapy when optimizing the treatment protocols for patients with lung cancer. But a review published in the Journal of Thoracic Oncology y (2015 Mar 30. [Epub ahead of print]) suggests that exercise should be added to the therapeutic mix. The review found that exercise reduces symptoms, increases exercise tolerance, improves quality of life and potentially reduces length of hospital stay and postsurgical complications for lung cancer patients. Investigators from the Medical University of South Carolina (MUSC) conducted a review of 42 studies that examined the effects of exercise on cancer outcomes, including 22 surgical studies, 11 medical studies and nine reviews. All of the studies focused primarily on lung cancer, although one medical study focused on a variety of metastatic cancers, and another focused on lung and colon cancer. The investigators concluded that physical activity is safe and beneficial for patients with all stages of cancer, as well as cancer survivors, and clinicians should encourage activity. Moreover, the MUSC team found that exercise may have beneficial effects on quality of life, physical function, social function and fatigue, and that these benefits extend to lung cancer survivors, as well. The investigators also found that most lung cancer patients, regardless of stage, want physical activity advice directly from a clinician at a cancer center before cancer treatment, and that exercise guidance may increase compliance with a dedicated program. While the ideal exercise program for patients with different stages of lung cancer remains unclear, the authors concluded “clinicians should (at minimum) consider physical activity early, counsel against inactivity, and encourage physical activity in all stages of lung cancer patients and lung cancer survivors.” “There are still large gaps in the published literature to be addressed and these could be filled with large definitive prospective trials that evaluate the benefit of exercise in lung cancer patients,” they added.

C. difficile Doubles Hospital Readmissions

atients with Clostridium difficile infection (CDI) are twice as likely to be readmitted to the hospital as patients without the diarrheal infection, according to a Detroit Medical Center study. Nearly a third of CDI patients were readmitted after 30 days versus 14.4% of all-cause discharges.

$373.9 Billion Spent On Drugs in 2014

rug spending in the United States last year was one for the record books. Pharmacists filled a record 4.3 billion prescriptions in 2014 that cost nearly $374 billion, for a 13.1% increase in spending over the prior year. One of the main drivers of growth was the explosive launch of Gilead’s new hepatitis C drug, Sovaldi, which racked up more than $10 billion in sales.

Breast Cancer Also Benefits

UV Light Robot Foils Superbugs

Lung cancer is not the only solid tumor that may benefit with the addition of exercise. Researchers in Bogota, Colombia have found that patients with breast cancer fare better in at least one outcome—cancer-related fatigue (CRF)—when physical activity is encouraged (BMC Cancer; published online Feb 21, 2015. doi: 10.1186/s12885-015-1069-4). The investigators looked at the pooled effects of supervised aerobic exercise on CRF in more than 1,000 breast cancer survivors. They found that patients in the exercise group had significantly reduced rates of fatigue when compared with patients given conventional treatment (standardized mean difference [SMD] = -0.55; 95% confidence interval, -1.09 to -0.01). The researchers concluded that “supervised exercise reduces CRF and must be implemented in breast cancer rehabilitation settings.” —Ajai Raj

obotics might be the answer to ridding hospitals of antimicrobial-resistant organisms. Texas researchers report that an ultraviolet light disinfecting robot cut the amount of bacteria in a hospital room by about 70%—roughly the same level of effectiveness as manual disinfection.

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

Frank Tagarello, Senior Art Director/Managing / Director, r MAX Graphics

Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 42 • Number 5 • May 2015 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL

INTERNAL MEDICINE

EDITORIAL STAFF

David S. Craig, PharmD, BCPS, Tampa, FL

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA

Robert L. Barkin, MBA, PharmD, Chicago, IL

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

BIOTECHNOLOGY

Jeffrey Norenberg, PharmD, Albuquerque, NM

Indu Lew, PharmD, Livingston, NJ

ONCOLOGY

Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

Robert T. Dorr, PhD, RPh, Tucson, AZ

CARDIOLOGY

Robert Ignoffo, PharmD, San Francisco, CA

C. Michael White, PharmD, Storrs, s CT CNS/PSYCHIATRY Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas Larry Ereshefsky, PharmD, San Antonio, T Texas COMPLEMENTARY AND ALTERNATIVE MEDICINE

Marie Rosenthal, MS, Senior Editor mrosenthal@mcmahonmed.com Kevin Horty, Don Pizzi, Adam Marcus, Contributing Editors

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

James Prudden, Group Editorial Director

Cindy O’Bryant, PharmD, Aurora, CO

Robin B. Weisberg, Manager, r Editorial Services

Ali McBride, PharmD, MS, BCPS, St. Louis, MO

Elizabeth Zhong, Associate Copy Chief

Sara S. Kim, PharmD, BCOP, New York, NY ORGAN TRANSPLANT PHARMACY

Cathy Rosenbaum, PharmD, Cincinnati, OH

Eric Tichy, PharmD, BCPS, New Haven, CT

CRITICAL CARE

PEDIATRICS

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

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4 Policy

Pharmacy Practice News • May 2015

PPN: The Conversation Another new pharmacy school?

Dean Jordan Makes the Case In the fall of 2015, Chapman University, a mid-sized private university in southern California, will enroll its first class of students in an eight-trimester accelerated Doctor of Pharmacy degree program at the University’s Harry and Diane Rinker Health Science Campus, in Irvine. The program will be the first school of pharmacy in Orange County. Its opening comes amid lingering concerns about the rapid growth of new pharmacy schools, including questions about the quality of the education being provided and the job prospects for graduates. To explore these and other timely topics in pharmacy education, Pharmacy Practice News talked with the school’s founding dean, Ronald Jordan, RPh, FAPhA, a former dean of the College of Pharmacy at the University of Rhode Island (URI). PPN: What do current projections for the pharmacy workforce look like, and are they enough to say for certain that your first graduating class will have a strong job market open to them? Ronald Jordan, RPh, FAPhA: Our work in planning this school was based on a number of optimistic views about future opportunities for pharmacists that came from operating a program in Rhode Island and seeing what was happening with our grads. We never had a problem with employment opportunities for our graduates there, who were always very well trained to be outstanding individuals. The level and type of education provided to students makes all the difference in whether they get employed afterward. Do a good job with them and they succeed. In California, the recent change in the SB 493 law that gives pharmacists the right to independently manage prescription drug therapy for a patient who has an existing diagnosis is a huge opportunity for changes in the structure of pharmacy practice that will lead to many new and almost unforeseen jobs for pharmacists. The mode of practice for pharmacies will change, so that the profession can be more involved in community health initiatives, discharge planning and management of prescription drug therapy. There are many opportunities for us to find new partnerships with other health care organizations and whole new ways for our graduating pharmacists to practice. PPN: How does your curriculum help distinguish Chapman from other pharmacy schools? Mr. Jordan: We’ve built this curriculum on two fundamentals: first, a very strong science base. We will open the school with about $3 million of funded research. Our faculty members are passionate about the research they’re doing and its effects on people’s lives. I find that good researchers who do state-ofthe-art work are some of the best teachers you can have. Second, I didn’t want a typical new startup pharmacy school, where the focus is totally on the existing practice of clinical pharmacy; instead, our goal

was to create a school with a curriculum and philosophy that also is focused on getting students to understand the broad range of opportunities within the medical device, pharmaceutical industry and other areas of work. I’ve talked to leaders in health care in Orange County about teaching students how to become high-performing team members—not just in hospitals and community pharmacies, but in managed care, government, the pharmaceutical industry and elsewhere. So, our second focus is really on what it takes to become a high-performing team member and make a difference in people’s lives.

School Achieves Highest Standards,” February 23, 2015] about how important accreditation is. We’re graduating people who will be making decisions that can affect people’s lives. The problem is that some schools have decided that they wanted to try to do this without making the level of investment necessary. To be accurate, very few schools have totally dropped their attempt to establish their program because of accreditation standards. Most schools are simply delayed in the process because they’re not making the level of investment and following the rules that the accrediting agency has set out.

‘You can’t have a “just-in-time” hiring mentality with health professionals who make decisions that can cause harm or death.’ —Ronald Jordan, RPh, FAPhA

As peers have visited, we have received compliments that we have developed one of the first schools of pharmacy that built its facility to closely match and support its mission and values. We have an active learning center where teams of students from multiple professions will work with faculty as guides, rather than the traditional sage on the stage. We are using a flipped classroom andragogy that has students going out to learn basic knowledge and gain understanding of concepts outside of class. They gather information and then come into class and, in small, team-based groups, work to apply that knowledge with faculty guidance. PPN: A few years ago, there were several new colleges of pharmacy that failed accreditation. Does that speak to a lack of quality in some of the newer schools, and do you see that as a persistent problem? Do you think the current accreditation process is rigorous enough? Mr. Jordan: The accreditation standards are there for good reason. I had an article in the Orange County Register [“Accreditation Ensures Pharmacy

Chapman, in contrast, spent more than $60 million, committing resources to hire faculty early enough to give them the time and support to prepare the curriculum. You can’t have a “just-in-time” hiring mentality with health professionals who make decisions that can cause harm or death. It’s not an easy process, and I understand why some are delayed. I calculated the odds, and about three in 10 schools make it through each step of the process on time. We were one of those that did, which made us proud. PPN: You mentioned that Chapman strives to get students out of the classroom and into clinical areas of practice. Can you describe a few typical examples? Mr. Jordan: The standards require that about 30% of a pharmacy school’s curriculum be actual experiential learning. We are gearing up to deliver that starting from the very first trimester in the program. Our accelerated program gets students out faster than a traditional four-year academic program with summers off, and immediately from their introductory pharmacy experience in the first trimester, our students will

be out in experiential settings, certified to do immunizations and supporting health fairs at some of our partner institutions. In the latter trimesters, they will have advanced practice experiences at all four major health care delivery agencies in Orange County, as well as elective places like pharmaceutical industry companies, government agencies and managed care. PPN: How do you overcome resistance to establishing experiential learning programs among hospitals and other organizations that say they don’t have the time and resources? Mr. Jordan: Here in Orange County, the number of institutions actually mentoring pharmacy students was very low—a few students were in these institutions here and there, but there was no organized, dependable flow of students aimed at adding value while learning. We’re offering our expertise, a plan and resources in mounting these experiential programs, which has been kind of daunting for them in the past. We’re going to make working with us as valuable as we can and as painless as possible for institutions that want to help students help them. I believe we’re going to be able to offer expanding services [that] people heretofore haven’t thought about. A residency program, if designed properly, delivers licensed practitioners who can improve services and execute new areas of health care delivery—things like antimicrobial stewardship or outpatient medication management—that they might not otherwise be able to focus on with their existing staff who are busy with day-today production. —Reported by Gina Shaw

Web Exclusive Soon after Chapman announced its opening, the school was criticized on social media for painting too rosy a picture of job prospects for its first graduating class. Scan the 2D barcode to read more on this controversy or load pharmacypracticenews.com/Chapman in your browser.

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6 Policy

Medication Safety

Industry, Patient Advocates At Odds on Gen Drug Labels HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VAZCULEP safely and effectively. See full prescribing information for VAZCULEP. VAZCULEP (phenylephrine hydrochloride) Injection for intravenous use Initial U.S. Approval: 1954 INDICATIONS AND USAGE VAZCULEP (phenylephrine hydrochloride) Injection is an alpha-1 adrenergic receptor agonist indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. DOSAGE AND ADMINISTRATION VAZCULEP (phenylephrine hydrochloride) Injection, 10 mg/mL, is injected intravenously either as a bolus or in a dilute solution as a continuous infusion. Dilute before administration. Dosing for treatment of hypotension during anesthesia • Bolus intravenous injection: 40 mcg to 100 mcg every 1-2 minutes as needed, not to exceed 200 mcg. • Intravenous infusion: 10 mcg/min to 35 mcg/min, titrating to effect, not to exceed 200 mcg/min. The dose should be adjusted according to the pressor response (i.e., titrate to effect). DOSAGE FORMS AND STRENGTHS • Injection • 1 mL single use vials containing 10 mg phenylephrine hydrochloride (10 mg/mL) • 5 mL pharmacy bulk package vials containing 50 mg phenylephrine hydrochloride (10 mg/mL) • 10 mL pharmacy bulk package vials containing 100 mg phenylephrine hydrochloride (10 mg/mL) CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS • Extravasation during intravenous administration may cause necrosis or sloughing of tissue • Severe bradycardia and decreased cardiac output • Allergic-type reactions: Sulﬁte • Concomitant use with oxytocic drugs: Pressor effect of sympathomimetic pressor amines is potentiated ADVERSE REACTIONS Most common adverse reactions during treatment: nausea, vomiting, and headache. To report SUSPECTED ADVERSE REACTIONS, contact Éclat Pharmaceuticals at 1-877-622-2320 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Agonistic effects with monoamine oxidase inhibitors (MAOI), oxytocin and oxytocic drugs, tricyclic antidepressants, angiotensin and aldosterone, atropine, steroids, norepinephrine transporter inhibitors, ergot alkaloids • Antagonistic effects with Ơ-adrenergic antagonists, phosphodies terase Type 5 inhibitors, mixed Ơ- and ơ-receptor antagonists, calcium channel blockers, benzodiazepines and ACE inhibitors, centrally acting sympatholytic agents USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm.

Revised: 7/2014

n late March, stakeholders gathered at an FDA meeting to debate a proposed rule that would allow generic drug companies to quickly update safety labeling without FDA approval. Currently, only brand-name companies have this authority. Representatives from Public Citizen, the National Center for Health Research, Consumers Union and other entities argued for passage of the FDA rule as written. A parade of individuals harmed by inadequately labeled generic drugs also testified in support, including a woman who lost her hand to gangrene after Phenergan was delivered by IV push and a woman disabled from ciprofloxacin. Supporters argue that once generics enter the market, brand-name market shares drop and manufacturers are less vigilant about labeling updates. Additionally, brand-name manufacturers often cease production of their product and then there is no one responsible for updating safety concerns. In the pivotal 2011 Pliva v. Mensing decision, the U.S. Supreme Court concluded that a generic company cannot be found liable when its labeling fails to include warnings about an adverse event, as long as the label matches brand-name labeling, even if a company is aware of potential problems. The Hatch-Waxman Act of 1984, which governs generic drugs, dictates that, with a few exceptions, generic drugs must carry the same label as their brandname counterparts. “Americans assume that they have the same legal protections and most up-todate safety information regardless of whether their drug is a brand name or not,” said Anna Mazzucco, PhD, scientific advisor at the National Center for Health Research. “The current situation creates a terrible double standard, making patients with generic drugs secondclass citizens.” Testifying against the proposed rule were officials from companies including Apotex, Mylan, Perrigo and Sandoz, who argued that the rule went against the sameness principle of the HatchWaxman Act, generic companies did not have adequate information to update labels and consumers would be confused by differing labels. “Patients are smart enough to understand why different labels may differ,” Dr. Mazzucco testified. “Temporary differences in labeling between generic and brand-name drugs are far outweighed by the benefit to public health that comes from updating labels with drug safety information as quickly as possible.”

Almost all generic drug companies are backing an alternative solution proposed by the Generic Pharmaceutical Association (GPhA) and Pharmaceutical Research and Manufacturers of America. They argue that after a generic manufacturer enters the market, neither the generic nor the brandname manufacturer should be able to update the safety warnings without first obtaining FDA approval. They ask that the FDA establish an expedited agency process for reviewing new safety information from a brand-name or generic drug manufacturer. The FDA would notify all drug manufacturers if the agency deemed a change was necessary and a labeling change would then be made within 30 days through e-labeling, available via the Internet. “In order to achieve parity, [the] FDA should take responsibility rather than making ANDA [abbreviated new drug application] holders responsible,” testified Candis Edwards, senior vice president of regulatory and clinical affairs, Amneal Pharmaceuticals. She argued that generic companies do not have complete information to make an informed label change. “If I have 10% of the market share, I don’t have access to the safety data generated by the other 90% of the consumers using a drug,” she said.

Increased Costs a Concern Industry representatives also argued that the proposed rule would greatly increase costs through increased liability exposure and that these costs would be passed on to consumers. A study sponsored by GPhA estimated the proposed rule would increase generic drug spending by 5.4% and cost the government and private payors $4 billion annually. This is vastly different from the FDA’s estimate of $26,000 annually, which analysts say is low because the agency didn’t include liability costs in its analysis. Still, several individuals who testified at the meeting discounted the GPhA study estimate. “If patients knew they could not rely on the accuracy of generic drug labels or seek legal remedies if harmed ... patients would demand brand-name drugs, and that would result in higher medical costs,” said Paul Brown, a representative of the Patient, Consumer, and Public Health Coalition. Michael Carome, MD, the director of Public Citizen’s Health Research Group, said the alternative solution would slow down communication of safety information and make companies less liable. A final rule is expected Sept. 30, 2015. —Kate O’Rourke

Policy 7

Pharmacy Practice News • May 2015

FDA Watch

FDA Grants Priority Review for Idarucizumab T

he FDA granted priority review to the Biologics License Application for idarucizumab (Boehringer Ingelheim Pharmaceuticals), which is being investigated to reverse the anticoagulant effect of dabigatran (Pradaxa, Boehringer Ingelheim), a novel oral anticoagulant, in patients needing emergency intervention or experiencing an uncontrolled or life-threatening bleed. Idarucizumab will be reviewed under an accelerated approval and is the first review for a reversal agent for this new drug class.

applications. The FDA instituted its Accelerated Approval program to allow earlier approval of drugs that both treat a serious condition and fill an unmet medical need. Additionally, the FDA granted Breakthrough Therapy Designation for idarucizumab in June 2014. Dabigatran is indicated to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the treatment of deep venous

new

The application includes Phase I data showing the potential for idarucizumab to provide immediate reversal of the anticoagulant effect of dabigatran. In these studies, no clinically relevant adverse events related to the drug were observed. Additionally, no procoagulant effect was observed after the administration of idarucizumab when measured by coagulation assay. Interim data from the ongoing RE-VERSE AD (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab) trial investigating idarucizumab in clinical settings, was also included in the application. Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific reversal agent for the anticoagulant effect of dabigatran in patients needing emergency surgery or urgent procedures or for life-threatening or uncontrolled bleeding events. The safety and efficacy of idarucizumab has not been established. “If approved, idarucizumab has the potential to be a significant evolution in care by providing physicians with an option for Pradaxa patients in rare emergency situations that may require rapid reversal of the anticoagulation effect of dabigatran,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim. A priority review designation is granted when a drug, if approved, could offer a significant improvement in the safety or effectiveness in treating serious conditions when compared with standard

thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for five to10 days; and to reduce the risk for recurrence of DVT and PE in patients who have been previously treated. “If approved, idarucizumab would represent a significant clinical advance in that it would allow for reversal of an oral anticoagulant. The fast track review is a clear indication that the FDA sees

it as an important and novel advance,” said Dan Mendelson, CEO of Avalere Health LLC, a consulting firm based in Washington, DC. “If an innovator can find ways to add value to existing products, as [Boehringer Ingelheim] is doing, they can create sustainable quality advantage, and the consumer will be willing to pay for value.” —PPN Staff

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8 Policy

Pharmacy Practice News • May 2015

Drug Development

BIOSIMILARS agency has not approved the former as “interchangeable” with the latter—only “highly similar” to it, experts noted. Sandoz did not seek the interchangeability designation from FDA, but even if the FDA granted it, a growing number of states are enacting laws to prevent pharmacists from substituting interchangeable biological generics for branded drugs in the same way they do generic chemical drugs for branded ones. This worries the FDA and professional pharmacy societies because the U.S. biosimilars market appears poised to take off with at least four more drugs awaiting marketing approval (sidebar). The National Community Pharmacists Association (NCPA) is one of the trade groups opposed to anti-substitution legislation. “We feel that state substitution laws for interchangeable biologics should be consistent with existing state laws for the substitution of traditional generic drugs,” said John Norton, NCPA public relations director. “Within the states, these bills often contain requirements that pharmacists must notify physicians should a biosimilar be dispensed instead of a brand biologic. Such unnecessary standards serve to undermine the FDA’s, which finds these bills to be premature.”

Source: Hospira.

continued from page 1

Although the process for manufacturing biologic products (in the case above from a human cell) is very complex, the FDA has standards in place to ensure that differences between a proposed biosimilar and its reference biologic will not be clinically meaningful.

drug. Amgen claimed Sandoz violated provisions of the Biologics Price Competition and Innovation Act (BPCIA), the 2010 law that established the biosimilar regulatory pathway ((Pharmacy Practice News Web exclusive, March 25,

‘[BPCIA] expressly states that an interchangeable biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.’ —Kristofer Baumgartner Shortly after the FDA’s approval of Zarxio in March, a U.S. District Court judge in San Francisco denied Amgen’s motion for a preliminary injunction to prevent Sandoz from marketing its

2015; http://goo.gl/YTunJS). The District Court ruling, which Amgen said it would appeal, gives Sandoz a green light to begin selling Zarxio, although many legal experts predict the company

How Will CMS Pay for Biosimilars?

he Affordable Care Act amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biologic products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDAlicensed biologic formulation. The Centers for Medicare & Medicaid Services (CMS) will incorporate biosimilars that are approved under the abbreviated biologic approval pathway into the average sales price payment methodology and issue additional guidance as necessary. Questions and answers related to this issue can be found in MLN Matters Special Edition Article SE1509, which is posted on the Outreach and Education section of the CMS.gov website at http://goo.gl/rjLS1k. —Bonnie Kirschenbaum

For more recent news affecting pharmacy payment, see the “Reimbursement Matters” column on pages 16 and 17.

will wait until after appeals litigation is resolved, a potentially lengthy process.

State Anti-Substitution Laws Currently, eight states—Delaware, Florida, Indiana, Massachusetts, North Dakota, Oregon, Utah and Virginia— have enacted laws that limit biosimilar substitution to those drugs that the FDA has deemed interchangeable. The state laws began to emerge several years ago as brand-name drug manufacturers, led by Amgen and Genentech, lobbied state legislatures to protect their products from the coming wave of biosimilar competition. Although provisions vary from state to state, substitution laws generally give physicians the ability to block biosimilar substitution by specifying the dispensing only of the branded drug. The laws also require the pharmacy to notify the prescriber and patient of any authorized

substitution, sometimes within a specified period; require the pharmacist and physician to maintain records of the substitution, sometimes for a specified period; and may require the pharmacist to explain cost or price differences. According to the National Conference of State Legislatures, at least 39 bills or resolutions have been filed in 23 states related to biologics or biosimilars as of March 30, 2015. During the past two years, substitution bills were filed but failed to pass in 13 states. The California legislature last year approved a substitution bill, but the governor vetoed it. This year, legislation appears to be moving forward in more than a halfdozen states. Bills in California and Illinois would allow substitution of interchangeable biologics if the prescribing physician does not prohibit it, the pharmacist provides notification and details of the switch, the cost of the biosimilar is less, the patient is informed and written records are maintained. Legislatures in Colorado, Maryland, New Jersey and North Carolina are considering similar bills. A measure approved by Georgia’s legislature would require pharmacists to add a note on the label declaring the product to be an interchangeable biosimilar. This requirement does not apply to drugs dispensed in hospital settings. As for the FDA’s view on state efforts to pass anti-substitution laws, “the [agency] does not have a position on any particular state legislation,” Mr. Baumgartner said. However, “it is important for everyone to approach these issues with an understanding of both the FDA’s expertise in this area and what the law requires for approval

Policy 9

Pharmacy Practice News • May 2015

Drug Development

HOPA Ofﬁcials Weigh in on Biosimilars’ Potential Austin, Texas—Although biosimilars introduce a new way to reduce hospitals’ drug spend, pharmacists must carefully weigh that discount with the total costs of putting the products on the formulary, according to Scott Soefje, PharmD, MBA, BCOP, the president and J. Michael Vozniak, PharmD, BCOP, the past president, of the Hematology/Oncology Pharmacy Association (HOPA).

are components where you would have to change the EMR to use the biosimilar. That impacts barcode medication administration, and most of these are tied back to the NDC [National Drug Code] number.” To avoid medication errors, right before a product is administered, it is barcoded, which references back to the EMR. To make those changes can be “a lot of work. It’s not as simple as ‘let’s

‘A big consideration is the price point, and it has to be significant enough to make a change.’ —J. Michael Vozniak, PharmD

Both oncology pharmacists sat down with Pharmacy Practice News at the 2015 annual conference of HOPA to talk about biosimilar adoption. “I think definitely, a big consideration is the price point, and it has to be significant enough to make a change. There are other things to factor in, such as inventory and changing your electronic medical record [EMR],” said Dr. Vozniak, who is the associate director of Pharmacy, Professional Practice, at the Hospital of the University of Pennsylvania, in Philadelphia. “There

order in this new product and put it on the shelf,’” Dr. Vozniak explained. “One of the pharmacists told us that they had 700 protocols in their EMR. Some of them have the drug, some don’t, but they would have to manually go through and look at all 700 protocols and adjust it if they added the drug to their formulary. And they said the drug might not be cheap enough for them to do that,” added Dr. Soefje, who serves as the director of pharmacy at the University Medical Center Brackenridge, in Austin. “There goes your savings.”

of biosimilar and interchangeable products.” BPCIA “expressly states that an interchangeable biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product,” he explained. The American Pharmacists Association (APhA) supports development of “therapeutically equivalent generic/biosimilar versions” of biologicals, according to spokeswoman Michelle Spinnler, a senior external communications manager. She added that the group’s 2004 position statement on anti-substitution laws remains relevant: “APhA supports state substitution laws which emphasize the pharmacists’ professional responsibility for determining, on the basis of available evidence … that the drug products they dispense are therapeutically effective.” Since 2013, the American Society of Health-System Pharmacists (ASHP) has adopted the position of “opposing the implementation of any state laws regarding biosimilar interchangeability prior to finalization of FDA guidance,” said Nicholas Gentile, the director of state grassroots advocacy and political action.

ASHP is “in the middle of our policy process and there may be changes to it after our House of Delegates meets in June,” Mr. Gentile told Pharmacy Practice News.

Industry’s Take Earlier this year, the FDA asked industry to comment on what data were needed to determine interchangeability. The

Another factor is that the reference product might become less expensive to a point that it would not be worth the added staff hours to change the protocols to add the biosimilar, they noted. “I think the biosimilars will drive down the cost of the reference products,” Dr. Vozniak said. This happened for tbo-filgrastim (Grannix, Cephalon), a biologic product that was approved before the new FDA biosimilar approval pathway was developed. “I think that will continue to happen as more biosimilars are introduced. It will drive the price of the branded product,” he said. Dr. Soefje said another cost consideration will be whether the biosimilar is approved for all the same indications as the reference product and if it is designated as interchangeable. If not, the formulary will have to carry both products, which would also affect cost-effectiveness. Some formularies will carry both; some will only carry the reference product.

Naming Convention Considerations Another important consideration is product name. Dr. Vozniak said HOPA has been vocal in the naming convention for the biosimilars. “We are advocating for a prefix to the name, rather than a suffix. The Sandoz

agency is expected to issue draft guidance on this matter in 2015. According to BPCIA, to demonstrate biosimilarity, drug sponsors must provide: • Analytical studies demonstrating that the product is “highly similar” to the reference product, notwithstanding minor differences in clinically inactive components;

A Peek into the Biosimilars Pipeline

o far, four biosimilar applications from three companies are pending before the FDA. They consist of Celltrion’s Remsima, a biosimilar of Johnson & Johnson’s monoclonal antibody Remicade (infliximab) for rheumatoid arthritis; Apotex’s Grastofil biosimilar of Amgen’s Neupogen (filgrastim); Apotex’s biosimilar of Amgen’s Neulasta (pegfilgrastim), a long-acting formulation to stimulate white blood cell production; and Hospira’s biosimilar version of Amgen’s Epogen and Janssen’s Procrit (epoetin alfa) to treat anemia. The FDA had scheduled and then postponed an advisory committee meeting in March to evaluate Remsima, its first monoclonal antibody biosimilar application. Celltrion, which already sells its biosimilar in Europe, said the FDA requested more information about the drug, part of a “normal process.” The company said it expects to receive marketing approval for Remsima by the third quarter of this year. —T.A.

product has a placeholder: ‘filgrastimsndz.’ Our concern with a suffix is that many EMRs have character limits, so the name may be truncated and you might not see the sndz to know which product this is,” Dr. Vozniak said. “We want it first, so you see that and can easily recognize that it is a biosimilar.” Dr. Soefje said that, although these products are supposed to be similar, pharmacists want to be able to track the drug that the patient is actually getting, in case there are unexpected outcomes or toxicities once the biosimilar is in widespread use. “They are complicated to make. We think they are similar. We think they are going to be the same thing, but we need to prove it. We want to be able to track the drug the patient is actually getting. So we want to look at the outcomes and look at the toxicity, to say, ‘yes, this is truly doing what we thought it would.’ Or ‘no, it is not what we thought it would do.’” If the name appears the same in the EMR and there is a rash of toxicities, the pharmacist might not know which product the patient received, Dr. Soefje added. —Marie Rosenthal Dr. Vozniak reported no relevant ﬁnancial conﬂicts of interest. Dr. Soefje has served as a consultant to Amgen.

• Animal studies (including toxicity assessments); • One or more clinical studies (including assessment of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity and potency in one or more appropriate conditions as the reference product. When it comes to interchangeability, manufacturers also must show that the proposed product is expected to produce the same clinical result as the reference product in “any given patient,” Mr. Baumgartner said. Most such products also will need to demonstrate that the risk in terms of safety or reduced effectiveness of alternating or switching between the interchangeable product and the reference product is not greater than the risk of using the reference product alone. The interchangeability hurdle for biosimilarity is considerably higher than that set for chemical generic formulations, but the FDA expects to receive at least one application for an interchangeable biosimilar this year. —Ted Agres

10 Policy

Pharmacy Practice News • May 2015

FDA Watch

FDA Releases Final Guidance On Abuse-Deterrent Opioids

he FDA released final guidance on the evaluation and labeling of abusedeterrent opioids. The guidance reflects the agency’s current thinking on how studies should be conducted and evaluated to determine if a given formulation has abusedeterrent properties, according to the FDA. The 26-page document is geared toward helping drug makers to develop opioids with potential abusedeterrent properties. It also contains recommendations for what labeling claims may be approved based on study results. “Development of abuse-deterrent products is a priority for the FDA, and we hope this guidance will lead to more approved drugs with meaningful abuse-deterrent properties,” said Janet Woodcock, MD, the director of the FDA’s Center for Drug Evaluation and Research, in a press release. “While abuse-deterrent formulations do not make an opioid impossible to abuse and cannot wholly prevent overdose and death, they are an important part of the effort to reduce opioid misuse and abuse.” The FDA said opioids could be abused and manipulated in a variety of ways to create a euphoric effect, so abuse-deterrent technology should target known or expected routes of abuse. A draft guidance on abuse-deterrent opioids was first issued by the FDA in January 2013 and broke down abuse-deterrent technology into six categories: • Physical/chemical barrier • Agonist/antagonist combinations • Aversion • Prodrug • Delivery system • Combination of two or more of the above The final guidance contains a new category, “novel approaches” that encompasses novel approaches or technology not captured in the previous categories. The FDA said it intends to take a flexible, adaptive approach to evaluating and labeling potential products because the field of abuse deterrence is relatively new, and the agency “expects that the market will foster iterative improvements in products.” “The science of abuse-deterrent medication is rapidly evolving, and the FDA is eager to engage with manufacturers to help make these medications available to patients who need them,” said Margaret A. Hamburg, MD, former FDA commissioner. “We feel this is a key part of combating opioid abuse. We have to work hard with industry to support the development of new formulations that are difficult to abuse but are effective and available when needed.” The guidance emphasized that any study designed to evaluate an opioid formulation’s abuse-deterrent properties should be “scientifically rigorous” and consider the following: appropriateness of positive controls and comparator drugs, outcome measures, data analyses to permit a meaningful statistical analysis and selection of study participants. The FDA recommended collecting data from each of the following premarket studies categories to obtain a full understanding of a product’s abuse potential: • Laboratory-based in vitro manipulation and extraction studies (category 1) • Pharmacokinetic studies (category 2) • Clinical abuse potential studies (category 3) The FDA noted that results from category 1 studies may affect the designs of the other two, and category 2 results may affect the design and need for category 3 studies. The guidance contains postmarket study recommendations for products that may be an exception to these criteria. The FDA recommended that the labeling should include information on a product’s abuse-deterrent properties—which is supported by data—to better inform health care professionals, patients and the public about a product’s abuse potential. The label should also make it clear that abuse is still possible. The agency said more research is needed at this time to develop better and safer opioids while reducing the risk for abuse and misuse. The FDA noted that this guidance does not apply to generic opioids and that this will be addressed in a future guidance. —PPN Staff

First Generic Copaxone Approved

he FDA approved Glatopa (Sandoz), the first generic version of Teva’s Copaxone (glatiramer acetate injection) once-daily therapy for multiple sclerosis (MS). Glatopa, a synthetic protein that stimulates myelin basic protein, is indicated for the treatment of patients with relapsing forms of MS, including those who have experienced a first clinical episode and have magnetic resonance imaging (MRI) features consistent with MS. Glatopa is dosed as a 20 mg/mL once-daily injection. Although the mechanism of action of this immunomodulator is not completely understood, it appears to block myelin damage caused by T cells. MS is a chronic, inflammatory, immune-mediated disease of the central nervous system (CNS) in which the immune system attacks the myelin, the fatty substance that surrounds and insulates nerve fibers, and sometimes the nerve fibers themselves, causing sclerosis. This damage disrupts communication between the brain and other parts of the body producing a wide variety of symptoms. MS is among the most common causes of neurologic disability in young adults and occurs more frequently in women than men. For most individuals with MS, episodes of worsening function (relapses) are initially followed by recovery periods (remissions). Over time, recovery periods may be incomplete, leading to progressive decline in function and increased disability. MS patients often

experience muscle weakness and difficulty with coordination and balance. Most people experience their first symptoms of MS between the ages of 20 and 40. For this approval, FDA scientists established a thorough scientific approach for demonstrating active ingredient sameness that considers the complexity of glatiramer acetate. In the clinical trials for Copaxone, the most common adverse reactions reported by those taking the drug were skin problems at the injection site (redness, pain, swelling and itching), vasodilation, rash, shortness of breath and chest pain. Glatopa was developed in collaboration with Momenta and will be produced entirely in the United States. —PPN Staff

CMS Finalizes 2016 Payment And Policy Updates for Medicare Health and Drug Plans

he Centers for Medicare & Medicaid Services (CMS) released final Medicare Advantage (MA) and Part D Prescription Drug program changes for 2016. The Rate Announcement finalizes changes in payments that will affect plans differently depending on their characteristics. On average, the expected revenue change is 1.25% without accounting for the expected growth in coding acuity that has typically added another 2%. The final revenue increase is larger than the February advance notice largely because the Medicare actuaries recently updated Medicare per-capita spending estimates for 2014 and 2015. Medicare per-capita spending in 2014, 2015 and 2016 is still expected to be below historical standards. CMS said that particular care was taken to ensure that plan sponsors have the right incentives to care for dual-eligible populations (those on Medicare and Medicaid) over the long term.

“These policies strengthen Medicare Advantage for current and future consumers by encouraging higherquality care,” said Andy Slavitt, acting CMS administrator. “As the Medicare Advantage marketplace continues to grow, consumers are getting access to better care through more choice and competition. Seniors and people with disabilities, including the dual-eligible population, will continue to have an extensive choice of plans, affordable premiums and better and more transparent information about provider networks and pharmacies.” Enrollments in and quality of the MA and the Part D Prescription Drug programs continue to grow and improve since the Affordable Care Act (ACA) became law, according to CMS. MA reached record high enrollment in 2010 with more than 16 million beneficiaries (30%) enrolled in an MA plan. (In 2010, there were 48 million total Medicare enrollees.) —PPN Staff

e l b a l i a v A w No

12 Policy

Pharmacy Practice News • May 2015

Care Transitions Team-based patient outreach fuels success

Keeping a Closer Eye on Post-Discharge Planning R

egulatory and financial pressures are forcing hospitals to ramp up their post-discharge strategy initiatives. Some of the pressure is coming from the Affordable Care Act (ACA); Section 2717 requires that hospitals report the results of their efforts to prevent hospital readmissions. Whether it’s patient education and counseling, comprehensive discharge planning or postdischarge reinforcement by an appropriate health care professional, federal officials want to know what hospitals are doing to keep patients out of the hospital—and how many health care dollars are being saved in the process, experts noted. David B. Nash, MD, the dean at the Jefferson School of Population Health in Philadelphia, said that when it comes to implementing effective post-discharge policies, timing is critical. “Adequate discharge instructions, making sure patients understand every aspect of their medications, getting the medication and confirming that they are taking it as soon as they leave the hospital” are all efforts that have to be put in place as early as possible, Dr. Nash said. Susan Stinson, the senior vice president of clinical operations at The Lash Group, an AmerisourceBergen Specialty Company, based in Frisco, Texas, said hospitals face many challenges when implementing discharge strategies, particularly regarding staff follow-up with the patient. “It really takes a dedicated team focused on following up [post-discharge],” Ms. Stinson said. “They may not be able to reach the patient the first time they call, and they need to track what the patient’s needs are.”

Charisse Coulombe, vice president of clinical quality for the American Hospital Association’s Health Research & Educational Trust, runs a federally funded project with 1,500 hospitals across 31 states called the Hospital Engagement Network program. “One of the topics that we are looking at with these hospitals is readmissions,” Ms. Coulombe said, adding that the facilities “are very engaged in the conversation and are really looking at and focusing in on what they can do to help prevent patients from coming back to the hospital unnecessarily.” Ms. Coulombe echoed Dr. Nash’s assertion that discharge starts the day that the patient is admitted. “They’re identifying patients who could be at high risk for readmission and they want to know that up front. They’re doing an assessment on the patient and they’re looking at their age, socioeconomic factors. We want to know if every patient has a pretty complex social system and family support or no family support or if they are homeless.”

There’s Help at Hand Fortunately, hospitals don’t have to work in a silo when developing care coordination strategies: Several groups have studied the issue and published helpful guidelines and reports. A case study developed by The Commonwealth Fund, for example, looked at four hospitals with 30-day readmission rates in the lowest 3% among all U.S. hospitals for at least two of three conditions (congestive heart failure, myocardial infarction or pneumonia), reported by the Centers for Medicare & Medicaid Services (CMS) from the fourth quarter

‘A pharmacist who is on the discharge planning team has the opportunity to … ensure that inappropriate polypharmacy does not occur.’ —Vicki Basalyga, PharmD, BCPS of 2007 through the third quarter of 2008. These case studies identified the following best practices: A focus on improving clinical quality and patient care, with the belief that reductions in readmissions will naturally occur as a result of these improvement efforts. Attention to discharge planning from the first day of patients’ stay, typically within eight hours of admission. This includes staff assessment of patients’ risk factors, needs, available resources, knowledge of disease and family support. In fact, two of the four hospitals in The Commonwealth Fund report scheduled follow-up appointments for most of their patients prior to discharge. Because of limited resources, the two other hospitals made follow-up appointments on an ad-hoc basis for the neediest patients. All hospitals coordinated with home health agencies and connected patients to community resources.

The Pharmacist’s Role Choosing the right staffers to spearhead care coordination is another key

Why Care About Care Coordination?

s hospitals consider best practices, there is no shortage of evidence to make the case for why improving discharge planning is imperative. The Agency for Healthcare Research and Quality’s report, “Care Transitions from Hospital to Home: IDEAL Discharge Planning Implementation Handbook” (http://goo.gl/Pz80eZ), cites a 2003 study on the incidence and severity of adverse events (AEs) affecting patients after discharge from the hospital. The report states that nearly 20% of patients experience an AE within three weeks of discharge. Of these AEs, 75% could have been prevented. Among the most common post-discharge complications: adverse drug events, hospitalacquired infections and procedural complications. To further drive home the point regarding the importance of reducing readmissions, Section 3025 of the Affordable Care Act (ACA) has mandated since 2012, that hospitals with higher-than-average readmission rates for Medicare patients who had been treated for at least one of three conditions (congestive heart failure, myocardial infarction or pneumonia) within the last 30 days, will be penalized. Other research points to specific patient populations that are particularly at risk from poor care coordination. A 2014

white paper by The Advisory Board Company, for example, revealed that prescription errors are especially prevalent in older patients who are more likely to take multiple medications and whose physiologic ability to absorb, process and respond to drugs has been altered by aging. In such patients, therefore, post-discharge medication reconciliation is an important issue for post-acute providers, the researchers noted. The Institute for Healthcare Improvement (ICI) also weighs in on this issue. The group suggests that continuity in patients’ medical care is especially critical following a hospital discharge. In its 2013 “How-to Guide: Improving Transitions from the Hospital to Community Settings to Reduce Avoidable Rehospitalizations” (http://goo.gl/LdGU6J), the ICI reported that for individuals with multiple chronic conditions, this transition takes on even greater importance. The guide notes that unplanned rehospitalizations may signal a failure in hospital discharge processes, patient care, the quality of care in the next community setting (office practices, home health care and skilled nursing facilities), and lack of appropriate care resources for high-risk patients. —A.V.

to successful outcomes. Vicki Basalyga, PharmD, BCPS, the director of the American Society of Health System Pharmacists’ (ASHP) Section of Clinical Specialists, said that pharmacists are uniquely qualified to provide discharge planning services, given their expertise in medication therapy management. Such pharmacists, she said, can take on a variety of roles in discharge planning, including reconciliation, monitoring and education. Many patients have medications discontinued or started during their hospital stay, Dr. Basalyga pointed out. “A pharmacist can reconcile both medication lists and determine if all medications that the patient is continuing or restarting at home have a clinical indication, do not have any significant interactions and therapeutic duplication does not occur,” she said. One such example is a patient who is given acid suppression therapy to prevent stress ulcers in the the ICU. In most cases, the acid suppression needs to be discontinued at discharge. “A pharmacist who is on the discharge planning team has the opportunity to catch this and to ensure that inappropriate polypharmacy does not occur,” she said. Bedside discharge counseling is another strategy to consider, Dr. Basalyga suggested. The encounters permit the pharmacist to review a medication regimen with the patient to ensure that the patient does not have any questions about medications that have been prescribed before. When managing pediatric patients, for example, pharmacists can teach a parent how to use oral syringes and what adverse medication effects to look for in a patient who cannot verbalize. “A pharmacist can also teach elderly patients the best way to time their medications,” she noted, “or what to do when a dose is missed.” —Anthony Vecchione

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14 Policy

Pharmacy Practice News • May 2015

Oncology

Options Expand for Treating Chemo-Induced Nausea A

combination drug for chemotherapy-induced nausea and vomiting (CINV), approved by the FDA in October, is now commercially available. Akynzeo, distributed and marketed by Eisai Inc. (under license of Helsinn Healthcare SA), is a fixed-combination capsule comprising two drugs: oral palonosetron, approved in 2008 to prevent nausea and vomiting during the acute phase of chemotherapy (within the first 24 hours), and netupitant, a new drug that prevents both side effects during the acute and delayed phases of chemotherapy, from 25 to 120 hours after treatment. “What’s really exciting is this is the first fixed-dose combination therapy that targets the two key pathways involved in nausea and vomiting: the 5-HT3 pathway [involved in the acute phase of nausea/vomiting], as well as the NK1 pathway [involved in the delayed phase of nausea/vomiting occurring one to five days after treatment],” said Kimia Kashef, PhD, the associate medical director of Eisai’s CINV franchise. “You’re going to get protection from nausea and vomiting after chemotherapy for up to five days, which is really unique.” “As a medical oncologist, I can tell you it is very challenging for physicians to deliver effective chemotherapy and make sure a patient will tolerate it well,” added RuiRong Yuan, MD, the vice president of Eisai’s Americas Oncology Medical Research & Strategy Division. “The nausea and vomiting induced by chemotherapy agents, especially some like cisplatin, is really [debilitating] for a patient and throughout [their drug regimen], they cannot eat, they cannot drink and dehydration is prevalent. This drug has a major advantage for me because it not only prevents acute nausea/vomiting” but also the delayed nausea and vomiting that sometimes cause patients to go to the emergency department for nausea relief.

Akynzeo, given an hour before chemotherapy, was evaluated in three studies of more than 2,000 patients, Dr. Kashef said. A Phase II trial ((Ann Oncoll 2014;25[7]:13401346) of 694 chemotherapy-naive patients given cisplatin for solid tumors found superior overall complete response (CR;

‘[Akynzeo] will decrease the pill burden for some patients because it has a combination of drugs that we would normally give separately.’ —Cindy O’Bryant, PharmD

no emesis or rescue medication) rates for Akynzeo compared with palonosetron alone (87.4%, 87.6% and 89.6% for 100, 200 and 300 mg of netupitant, combined with 0.50 mg of palonosetron vs. 76.5% for palonosetron alone; P<0.05). A Phase III trial ((Ann Oncoll 2014;25: 1328-1333) with 1,455 chemotherapynaive patients receiving moderately emetogenic drugs (anthracycline-cyclophosphamide) comparing a combination

dose of 300 mg of netupitant plus 0.50 mg of palonosetron to palonosetron alone found the percentage of patients with CR significantly higher among patients taking Akynzeo. In the delayed phase (25120 hours after chemotherapy), 76.9% of patients had CR versus 69.5% of those receiving palonosetron ((P=0.001); in the overall phase (0-120 hours after chemotherapy), 74.3% of patients had CR versus 66.6% of those receiving palonosetron ((P=0.001); and in the acute phase (0-24 hours after chemotherapy), 88.4% of patients had CR versus 85% of those receiving palonosetron ((P=0.047). A second Phase III trial (Ann ( Oncol 2014;25[7]:1333-1339), with 413 chemotherapy-naive patients, evaluated a single oral dose of combination therapy netupitant 300 mg plus 0.50 mg of palonosetron that was given on day 1 with oral dexamethasone, compared with a three-day aprepitant regimen with palonosetron and dexamethasone. Patients completed 1,961 total chemotherapy cycles (76% moderately emetogenic and 24% highly emetogenic); 75% completed at least four cycles. The most frequent adverse events (AEs) from Akynzeo were constipation (3.6%) and headache (1.0%); most were mild to moderate, and there were no cardiac safety concerns. Overall CR rates (0-120 hours after chemotherapy) in cycle 1 were 81% for Akynzeo and 76% for the control regimen. Common AEs in the clinical trials were headache, weakness (asthenia), fatigue, indigestion, constipation and erythema. Studies showed that patients often receive antiemetic drug regimens that are inconsistent with CINV treatment guidelines, which call for multiple pathway–targeted antiemetic prophylaxis including an NK1 receptor antagonist, a 5-HT3 receptor antagonist and dexamethasone, Dr. Kashef said. Dexamethasone doses should be reduced when given with Akynzeo, according to an

Eisai press release. The wholesale acquisition cost of Akynzeo is $476 per dose, although individual patient costs are determined by health insurance coverage. Savings cards and patient assistance programs are available. For more information, see www.eisaireimbursement.com/Akynzeo.

Decreased Pill Burden a Plus Akynzeo provides added options for patients with CINV and “will decrease the pill burden for some patients because it has a combination of drugs that we would normally give separately,” said Cindy O’Bryant, PharmD, an associate professor of clinical pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Aurora. “If you look at the data, [Akynzeo] appears to have similar efficacy compared to similar antiemetics in the marketplace.” A concern with NK1 receptor agonists is the potential for drug–drug interactions and this is no different for Akynzeo, Dr. O’Bryant said. Clinicians should use caution in patients receiving other medications or chemotherapeutic agents metabolized by the cytochrome P450 3A4 pathway, such as midazolam or docetaxel, she noted. Another important factor to consider in the use of this agent will be to see what the uptake will be by guidelines put out by the National Comprehensive Cancer Network and others, and what insurance will cover, Dr. O’Bryant said. Akynzeo may be more cost-effective because other antiemetic medications are not necessarily needed in the days following chemotherapy, she said, “but that remains to be seen.” —Karen Blum Drs. Kashef and Yuan are employees of Eisai. Dr. O’Bryant reported no relevant ﬁnancial conﬂicts of interest.

FDA Approves Opdivo for Metastatic Squamous NSCLC

he FDA granted a new indication for nivolumab (Opdivo, BristolMyers Squibb) to treat patients with metastatic squamous non-small cell lung cancer (NSCLC) whose disease progresses during or after platinumbased chemotherapy. Nivolumab, a monoclonal antibody, binds to the PD-1 receptor and blocks its interaction with programmed death ligand-1 (PD-L1) and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response.

Nivolumab was approved in December 2014 for the treatment of previously treated unresectable or metastatic melanoma. The new indication was based in part on a Phase III, open-label, randomized, multinational clinical trial that compared nivolumab (3 mg/kg IV over 60 minutes every two weeks) in 135 patients with the standard of care—docetaxel (75 mg/m2 every three weeks) in 137

patients. All of the patients had metastatic squamous NSCLC who had progressed during or after platinum doublet chemotherapy. The trial did not exclude patients based on PD-L1 status. The primary end point was overall survival (OS). The prespecified interim analysis was conducted when more than 85% of the planned number of events for final

analysis was observed. The median OS was 9.2 months in the nivolumab arm (95% confidence interval [CI], 7.3-13.3) and six months in the docetaxel arm (95% CI, 5.1-7.3). The hazard ratio was 0.59 (95% CI, 0.44-0.79; P=0.00025). This hazard ratio translates to a 41% reduction in the risk for death with nivolumab compared with docetaxel. The most common adverse events were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea and constipation.

More than 1,700,000 potential compounding errors identified. 1

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16 Policy

Pharmacy Practice News • May 2015

Reimbursement Matters

Creating an E-Library: A Cache for More Cash? I

n this era of rapidly changing health care delivery and payment models, it’s critical to have an e-library to fall back on when making decisions about how to handle particular issues. From a payment standpoint, first up would be MLN Matters published by CMS. MLN Matters are national articles designed to inform health care professionals about the latest changes to CMS programs. Articles are prepared in consultation with clinicians, billing experts and CMS subject matter experts and are tailored, by content and language, to specific provider type(s) who are affected by complex program changes. The archived database of publications resides on the CMS.gov website (http:// goo.gl/byB3Lj) and is searchable. It’s easy to stay current with code changes and other interpretations of CMS rules using the agency’s MLN Matters publications. Although your hospital’s revenue cycle team of coders receives these updates, having access to your own e-library often will give you the background and rationale needed to put change into place. To subscribe to this free service, visit https://list.nih. gov/cgi-bin/wa.exe?A0=mlnmatters-l and select “subscribe” under the options tab on the right side of the page. A recent MLN Matters issue (Number: ( MM9097) contained a treasure trove of information illustrating the usefulness of the articles. Several pertinent to pharmacy are excerpted here, and in each case point out something to take note of.

Table 1. Drugs and Biologics With OPPS Pass-Through Status Effective April 1, 2015 HCPCS Code

Short Descriptor

Long Descriptor

APC

Status Indicator

C9445

C-1 esterase, Ruconest

Injection, c-1 esterase inhibitor (human), Ruconest, 10 units

9445

C9449

Inj, blinatumomab

Injection, blinatumomab, 1 mcg

9449

C9451

Injection, peramivir

Injection, peramivir, 1 mg

9451

C9452

Inj, ceftolozane/ tazobactam

Injection, ceftolozane/ tazobactam, 5 mg

9452

C9448

Oral netupitant palonosetron

Netupitant (300 mg) and palonosetron (0.5 mg), oral

9448

C9450

Fluocinolone acetonide implt Injection

Fluocinolone acetonide intravitreal implant, 0.19 mg

9450

CDM descriptions; the long descriptor is essential! But often the short descriptor is all that your PDM updates or revenue cycle team makes available. Don’t be frustrated; go to the master tables and get the info you really need.

Check out netupitant in Table 1, to see that HCPCS codes paid under Part B also may include oral medications. Also note that flucinolide implants for ophthalmic use products have more than one code. The generic listing for

A Reimbursement Lexicon APC: ambulatory payment classification CDM: charge description master CMS: Centers for Medicare & Medicaid Services

Master Tables Can Be Helpful

HCPCS: Healthcare Common Procedure Coding System

Notice that the short descriptor column in Table 1 doesn’t have enough information to be able to understand how to bill and how to set up your PDM and

OPPS: Outpatient Prospective Payment System PDM: pharmacy drug master

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

the drug is provided in Table 1. But in this case, further instructions also are given for a brand-specific product: HCPCS code C9450 is associated with Iluvien and should not be used to report any other fluocinolone acetonide intravitreal implant (for example, Retisert). Hospitals should note that the dosage descriptor for Iluvien is 0.01 mg. Because each implant is a fixed dose containing 0.19 mg of fluocinlone acetonide, hospitals should report 19 units of C9450 for each implant..

Keep an Eye Out for Status Indicator Changes … Can status indicators change during the year? Yes! CMS may revise its payment decisions and change the status indicator to let you know about the update. Revised Status Indicators (SIs) for two codes were effective April 1. The status indicator for HCPCS code J0365 (injection, aprotonin, 10,000 kiu) changed from SI=K (paid under OPPS; separate APC payment) to SI=E (not paid by Medicare when submitted on outpatient claims [any outpatient bill type]). The status indicator for HCPCS code J7189 (injection, factor xiii (antihemophilic factor, human), 1 i.u.) changed from SI=N (paid under OPPS; payment is packaged into payment for

Join the Conversation Pharmacy Practice News recently sat down with Bonnie Kirschenbaum, MS, FASHP, and Ernie Anderson Jr., MS, RPh, two long-standing PPN columnists, to discuss the latest trends affecting pharmacy reimbursement. Ms. Kirschenbaum draws on her extensive experience presenting on the topic at major medical and pharmacy associations and her work as a consultant. Mr. Anderson is a veteran of the payment “wars,” having been a pharmacy director at two health systems and a frequent testifier before Congress on payment issues that affect the profession. Click on the 2D barcode to access or visit www.pharmacypracticenews.com/BonnieErnie2015.

Policy 17

Pharmacy Practice News • May 2015

Reimbursement Matters other services) to SI=K (paid under OPPS; separate APC payment). See Table 2 for definitions of status indicators.

… And HCPCS Code Changes Can HCPCS codes change during the year? Yes! In the following case a C code, usually considered somewhat temporary, has been replaced by a Q code: Effective April 1, 2015, HCPCS code Q9975 will replace C9136. Notice that the short description also changed from factor viii (Eloctate) to Factor VIII FC Fusion Recomb. Both the long descriptor (injection, factor viii, fc fusion protein, [recombinant], per i.u.) and the SI (G, “Pass-Through Drugs and Biologicals.”) remained the same. Are new codes added periodically? Yes! Table 3 illustrates not only new additions but also effective dates that reach back several months.

Changes to Inpatient-Only List Effective April 1, 2015 Here’s another potential problem area: inpatient-only procedures that are provided to a patient in the outpatient setting on the date of the inpatient admission or during the three calendar days (or one calendar day for a non-subsection [d] hospital) preceding the date of the inpatient admission that would otherwise be deemed related to the admission. According to CMS policy for the payment window for outpatient services, such procedures will be treated as inpatient services, will be covered by CMS and are eligible to be bundled into the billing of the inpatient admission.

Collecting Information On Site-of-Service Charges The OPPS Final Rule for CY 2015 introduced methods for collecting information on site of service and related charges by requiring a reported modifier (PO). This was designed to determine whether site of service at an off-campus provider-based department (PBD) influenced the charge itself. CMS has finalized the instructions related to the reporting of the “PO” modifier (the short descriptor “Serv/proc off-campus pbd,” and the long descriptor “Services, procedures and/or surgeries furnished at off-campus providerbased outpatient departments”). The “PO” HCPCS modifier is to be reported with every code for outpatient hospital services furnished in an off-campus PBD. Reporting of this new modifier will be voluntary for one year (CY 2015), with reporting required beginning on Jan. 1, 2016. The modifier should not be reported for remote locations of a hospital, satellite facilities of a hospital or for services furnished in an emergency department. I hope that this introduction spurs you to think about creating an e-library. Future columns will have more suggested sites to review. ■

Table 2. Payment Status Indicators Indicator

Item/Code/Service

OPPS Payment Status

Services furnished to a hospital outpatient that are paid under a fee schedule or payment system other than OPPS

Not paid under OPPS. Paid by fiscal intermediaries under a fee schedule or payment system other than OPPS

Codes that are not recognized by OPPS when submitted on an outpatient hospital Part B bill type (12x and 13x).

Not paid under OPPS

Inpatient procedures

Not paid under OPPS. Admit patient. Bill as inpatient

Discontinued codes

Not paid under OPPS or any other Medicare payment system

Items, codes, and services: • That are not covered by Medicare based on statutory exclusion. • That are not covered by Medicare for reasons other than statutory exclusion. • That are not recognized by Medicare but for which an alternate code for the same item or service may be available. • For which separate payment is not provided by Medicare.

Not paid under OPPS or any other Medicare payment system

Corneal tissue acquisition, certain CRNA services and hepatitis B vaccines

Not paid under OPPS. Paid at reasonable cost

Pass-through drugs and biologics

Paid under OPPS; separate APC payment includes pass-through amount

(1) Pass-Through Device Categories (2) Radiopharmaceutical Agents

(1) Separate cost-based pass-through payment; not subject to coinsurance. (2) Separate cost-based non–pass-through payment

(1) Non–pass-through drugs, biologics (2) Brachytherapy sources (3) Blood and blood products

(1) Paid under OPPS; separate APC payment (2) Paid under OPPS; separate APC payment (3) Paid under OPPS; separate APC payment

Influenza vaccine Pneumococcal pneumonia vaccine

Not paid under OPPS. Paid at reasonable cost; not subject to deductible or coinsurance

Items and services not billable to the fiscal intermediary

Not paid under OPPS

Items and services packaged into APC rates

Paid under OPPS; payment is packaged into payment for other services, including outliers. Therefore, there is no separate APC payment

Partial hospitalization

Paid under OPPS; per diem APC payment

Packaged services subject to separate payment under OPPS payment criteria

Paid under OPPS

Significant procedure, not discounted when multiple

Paid under OPPS; separate APC payment

Significant procedure, multiple reduction applies

Paid under OPPS; separate APC payment

Clinic or emergency department visit

Paid under OPPS; separate APC payment

Nonimplantable durable medical equipment

Not paid under OPPS. All institutional providers other than home health agencies bill to DMERC

Ancillary services

Paid under OPPS; separate APC payment

Table 3. Recently Added Codes of Note CPT Code

CY 2015 SI

Effective Date

Meningococcal recombinant protein and outer membrane vesicle vaccine, serogroup B, 2-dose schedule, for intramuscular use

2/1/2015

Menb rlp vaccine im

Meningococcal recombinant lipoprotein vaccine, serogroup B, 3-dose schedule, for intramuscular use

2/1/2015

Dtap-ipv-hib-hepb vaccine im

Diphtheria, tetanus toxoids, acellular pertussis vaccine, inactivated poliovirus vaccine, Hemophilus influenzae type B PRPOMP conjugate vaccine, and hepatitis B vaccine (DTaP-IPV-Hib-HepB), for intramuscular use

1/1/2015

Short Descriptor

Long Descriptor

90620

Menb rp w/omv vaccine im

90621 90697

18 Policy

Pharmacy Practice News • May 2015

Ethics

KILLING DRUGS continued from page 1

ASHP’s current policy states that the decision “is one of individual conscience,” and adds that “pharmacists, regardless of who employs them, should not be put at risk of any disciplinary action, including loss of their jobs, because of refusal to participate.” But at an all-day meeting in April, the ASHP board of directors decided to advance a possible change in policy to the organization’s Council on Pharmacy Practice—the first of several review steps that a new policy must clear before being voted on by the House of Delegates at the ASHP’s Summer Meetings in Denver, June 6-10. Kasey Thompson, PharmD, MS, MBA, vice president of the Office of Policy, Planning and Communications, told Pharmacy Practice News that it was “premature” to discuss the views expressed at the board meeting, but added that “there is a clear recognition that this issue is pretty high in the public mindset and public debate, and there is a clear understanding where many health care organizations are on this issue.” The ASHP board’s action follows on the heels of a resolution by the American Pharmacists Association (APhA) that “discourages” pharmacists from taking part in executions “on the basis that such activities are fundamentally contrary” to their role as health care providers. Thomas E. Menighan, BSPharm, MBA, ScD (Hon), APhA executive vice president and chief executive, issued

a statement saying that pharmacist involvement “conflicts with the profession’s role on the health care team.” The new policy aligns APhA with other major health care organizations, including the American Medical Association, the American Nurses Association and the American Board of Anesthesiology.

pharmacies to fill the void. A handful of highly publicized executions in which supposedly lethal injection boluses failed to produce rapid and nearly painless deaths have also served to trigger re-examination of policies. The drugs used in executions include controlled medications often admin-

‘Pharmacists belong in the same realm as doctors and nurses. They don’t do exactly the same thing, but their ethical obligations to patients are similar.’ —Nancy Berlinger, PhD A week earlier, the International Academy of Compounding Pharmacists’ board of directors took a similar stance, discouraging members “from participating in the preparation, dispensing or distribution of compounded medications for use in legally authorized executions.” The board recognized, however, that it was the right of individual pharmacists to determine whether to participate “based upon his or her personal, ethical or religious beliefs.”

Compounders at Center Of Controversy Over the past year and a half, the issue has emerged as a top concern for pharmacists. The main reason is that as pharmaceutical manufacturers halted distribution of drugs for executions, states with capital punishment laws have called on compounding

istered to reduce anxiety and induce sedation for surgical procedures, such as pentobarbital, sodium thiopental and midazolam. Pancuronium bromide and potassium chloride also have been used as secondary agents in executions to cause paralysis and stop the heart. States have taken various approaches to the issue, according to Carmen Catizone, MS, RPh, DPh, the executive director of the National Association of Boards of Pharmacy. “There are probably three camps that we see,” he said. “First, there are states like North Carolina whose regulations say that the preparation of these types of medications for executions is not part of the practice of pharmacy. Then there are states like Texas that say it’s up to the pharmacist to decide whether or not to participate. States in the third group don’t have any policy and are struggling to decide which way to go.”

Because the issue remains controversial, pharmacists who might be willing to participate in executions, as well as others who would not take part but favor conscience-based decisions, tend not to express their beliefs publicly. Dr. Catizone said he knew “for certain” that there are pharmacists who believe in the death penalty, in states where it is legal, who say they “should have a right to participate even though it is directly opposite to the purpose of medication and what pharmacists should do. “I’ve not met or talked to anyone personally that espouses that,” he added, “but I know they exist.” William Fassett, PhD, RPh, professor emeritus at Washington State University College of Pharmacy in Spokane, who was the lead author of the new business item that brought the policy before the APhA House of Delegates, told Pharmacy Practice News that “it shouldn’t surprise people that once the issue arose, it was pretty much a routine decision by pharmacists” to join other health care providers whose policies oppose participation in executions. “Executing people with chemicals isn’t health care,” said Dr. Fassett, who is an expert in health care ethics and law. (For more on the ethics of participation, see sidebar.) That belief is generally supported by health care professionals, whether they favor capital punishment or oppose it. Moreover, organizations like APhA and others emphasize that their members are free to make their own ethical choices. And indeed some physicians see KILLING DRUGS, page 20

Botched Executions: An Argument for or Against Pharmacist Involvement?

ven though an increasing number of professional organizations are taking a clear position on capital punishment and encouraging members to not participate in executions, some bioethicists argue that a case can be made for a degree of involvement by pharmacists and other caregivers. “On one hand, assisting in an execution requires that a health care provider kill an individual, likely against [his or her] will, but on the other hand, health care providers are uniquely skilled in the ‘safe’ delivery of lethal substances,” said Dien Ho, PhD, an associate professor of philosophy and health care ethics in the School of Arts and Sciences at MCPHS University in Boston. “The right medical professional knows how to find a vein properly, how to create the precise lethal cocktail that minimizes suffering and how to ensure the convicted person is, in fact, dead.” Indeed, some believe it was the absence of an appropriately trained professional that left Oklahoma inmate Clayton Lockett writhing without adequate sedation through a lethal injection that took four times as long as typical executions in that state do (“Secrets Still Shroud Clayton Lockett’s Execution,” Tulsa World, May 11, 2014). According to the official execution report, failed IV access was the single greatest factor that contributed to the botched death (http://goo.gl/ jc5lyh). As some experts have pointed out, it was a phlebotomist that failed to insert the line

properly; not only does the phlebotomist’s credentials remain secret under state law, the profession of phlebotomy does not require special state certification in Oklahoma.

decision that should be respected by the citizenry. “Health care providers can and should participate in the public discussion on the topic, but the bottom line is that if the state permits executions,

‘If the State permits executions, pharmacists and other providers can play a role in ensuring it’s conducted in a manner that’s not cruel and unusual.’ —Bruce White, DO, JD Errors such as poorly placed or dislodged lines— which were also implicated in the botched executions of Angel Nieves Diaz in 2006 and Romell Broom in 2009—behoove skilled professionals to step in and help make executions as painless as possible, argued Bruce White, DO, JD, a pharmacist, attorney and pediatrician as well as director of Alden March Bioethics Institute at Albany Medical College in Albany, N.Y. “It’s worth noting that the guillotine replaced more painful methods of execution only after Dr. Guillotin recommended a more humane form of capital punishment,” he said. Dr. White added that although he is personally opposed to capital punishment, whether or not to institute or outlaw the practice is a public policy

pharmacists and other providers can play a role in ensuring it’s conducted in a manner that’s not cruel and unusual.” In contrast, James Ruble, PharmD, JD, an associate clinical professor in the Department of Pharmacotherapy at the University of Utah College of Pharmacy in Salt Lake City, believes the professional commitment of pharmacists and other providers to patient care is incompatible with using their skills to execute individuals. Dr. Ruble, who submitted an affidavit on behalf of Tennessee’s death row inmates that challenged that state’s use of lethal injection, also noted that it is difficult to determine whether pharmacies that compound see BOTCHED, page 21

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20 Policy

Pharmacy Practice News • May 2015

Ethics

KILLING DRUGS continued from page 18

and nurses have taken part in executions despite their associations’ codes of ethics opposing the practice ((N Engl J Med 2006;354:1221-1229). Dr. Fassett pointed out that compounding drugs for lethal injection might even be seen as illegal under the 2013 federal Drug Quality and Security Act, which requires that traditional compounding pharmacies possess a valid physician prescription for a patient before dispensing a drug, as well as U.S. drug enforcement rules that prohibit physicians from prescribing controlled medications like pentobarbital and sodium thiopental for other than therapeutic purposes.

‘Executing people with chemicals isn’t health care.’ —William Fassett, PhD, RPh However, states that use pharmacistcompounded drugs for executions have tended to rely on their state laws to justify their decisions. In Texas, for example, Gay Dodson, RPh, the executive director/secretary of the Texas State Board of Pharmacy, said the state “has a law that allows pharmacists to compound for what is called office use. True, it is in direct violation of federal law, but it is our law. Our legislature passed it.” Nancy Berlinger, PhD, a research scholar at The Hastings Center in Garrison, N.Y., who follows ethical decision making in the health care professions, said the APhA’s policy revision “is coming at a time when capital punishment in the United States is under high scrutiny. “We’ve seen these reports,” she said, “about executions being botched in horrible ways. The governors [of some states] have actually suspended the implementation of capital punishment because they’ve said we just can’t guarantee that we’re not crossing the line into cruel and unusual punishment.” Dr. Berlinger said the APhA’s new policy “clarifies further” that pharmacists are health care professionals with “an explicit obligation to the person who is going to be receiving the medication.” Over the past decade, she added, “pharmacists have become more and more involved in patient safety, in palliative care and the use of drugs to treat pain and other symptoms. So a pharmacist in a hospital, for instance, might be a member of a palliative care team or a patient safety team, further articulating the fact that pharmacists belong in the same realm as doctors and nurses. They don’t do exactly the same thing, but

their ethical obligations to patients are similar.” John Poikonen, PharmD, vice president of clinical content at Medproof, who vehemently opposes pharmacists’ participation in executions, has posted comments on Twitter criticizing ASHP for not bringing its policy up to date. In one, he tweeted, “New policy by APhA on execution makes ASHP official position look even more irrelevant and out of touch.” Dr. Poikonen’s opposition to the death penalty was formed, he said, in the late 1980s during a drug distribution consult

at the California Institution for Men in Chico, where he viewed the prison’s death row ward. “It was really disturbing,” he told Pharmacy Practice News. “Did you see ‘The Green Mile’? It was not dissimilar to that, minus the dirt floor.” That was when he decided, he said, that if he were ever put in that position, he “would not participate.” Pharmacists who have participated in executions tend to seek anonymity to avoid the exposure that can lead to hounding by the media and public derision. In Texas, for example, Ms. Dodson

said the compounding pharmacist who supplied the batch from which the lethal injection for the most recent execution was drawn was not identified. “I have no idea who it was,” she said, “and frankly I don’t want to know.” Moreover, she said, the state legislature was weighing a bill in April that would allow corrections officials to withhold the identities of pharmacists, physicians and others involved in executions, exempting them from the state’s Open Records Act. —Bruce Buckley

Policy 21

Pharmacy Practice News • May 2015

Ethics

BOTCHED continued from page 18

drugs for lethal injection are appropriately preparing these agents. “Pharmacies that prepare lethal injection chemicals are often shielded under anonymity laws and state capital punishment protocols,” he said. “And even if the agents are prepared properly, lethal injection protocols have not been—and cannot be—studied ethically in a randomized,

controlled fashion, so we don’t have the data demonstrating humaneness.” Evaluating humaneness also is made difficult by the use of paralytic agents, such as pancuronium bromide, which other experts have argued can mask pain and suffering, serving more to “allow the living to walk away thinking that the most severe punishment was delivered as humanely as possible” (“Fatally Flawed,” Time May 16, 2014). Dr. Ho reiterated that protesting against capital punishment and participating in the practice to ensure

humaneness are not mutually exclusive goals. “There is nothing that prevents a health care provider from expressing or even lobbying actively against the killing or the participation in the killing of an individual, while at the same time ensuring that execution is done humanely,” he said. “Assisting with an execution to ensure that it minimizes suffering is akin to participating in a needle exchange program. Although one is not necessarily condoning the practice, a health care provider can help

alleviate needless suffering.” —David Wild

What’s Your View? What key factors do you think should be weighed when deciding whether the pharmacy profession should play a role in the compounding or administration of drugs for lethal injections? Send your comments to davidb@mcmahonmed.com.

22 Clinical

Pharmacy Practice News • May 2015

Hospital Readmissions

Keeping Bariatric Patients From Coming Back

ith the risk for death from bariatric surgery now lower than that for hip replacement surgery, the bariatric surgery community is enlisting pharmacists to help achieve a new goal: reducing readmissions after the procedure. “I see pharmacists taking on a bigger role in care of bariatric surgical patients going forward,” said Bishoy Luka, PharmD, BCNSP, the director of Clinical Pharmacy Services and

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegﬁlgrastim) injection, for subcutaneous use

Education, North Shore University Hospital, Manhasset, N.Y. Dr. Luka is one of a group of clinical pharmacists working with the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP), an initiative that establishes national standards for facilities and surgeons performing bariatric surgery. Earlier this year, MBSAQIP launched a national quality improvement project,

The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving INDICATIONS AND USAGE docetaxel 100 mg/m2 every 21 days (Study 3). A total of 928 Neulasta is indicated to decrease the incidence of infection, as patients were randomized to receive either 6 mg Neulasta manifested by febrile neutropenia, in patients with nonmyeloid (n = 467) or placebo (n = 461). The patients were 21 to 88 years malignancies receiving myelosuppressive anticancer drugs of age and 99% female. The ethnicity was 66% Caucasian, 31% associated with a clinically significant incidence of febrile Hispanic, 2% Black, and < 1% Asian, Native American or other. neutropenia. Bone pain and pain in extremity occurred at a higher incidence Neulasta is not indicated for the mobilization of peripheral blood in Neulasta-treated patients as compared with placebo-treated progenitor cells for hematopoietic stem cell transplantation. patients. CONTRAINDICATIONS Table 1. Adverse Reactions With ≥ 5% Higher Incidence Do not administer Neulasta to patients with a history of serious in Neulasta Patients Compared to Placebo in Study 3 allergic reactions to pegfilgrastim or filgrastim. System Organ Class Neulasta 6 mg Placebo WARNINGS AND PRECAUTIONS SC on Day 2 (N = 461) Preferred Term Splenic Rupture (N = 467) Splenic rupture, including fatal cases, can occur following the Musculoskeletal and connective tissue disorders administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal Bone pain 26% 31% or shoulder pain after receiving Neulasta. Pain in extremity 4% 9% Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients Leukocytosis 9 receiving Neulasta. Evaluate patients who develop fever and In clinical studies, leukocytosis (WBC counts > 100 x 10 /L) lung infiltrates or respiratory distress after receiving Neulasta, for was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable ARDS. Discontinue Neulasta in patients with ARDS. to leukocytosis were reported in clinical studies. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in Immunogenicity As with all therapeutic proteins, there is a potential for patients receiving Neulasta. The majority of reported events immunogenicity. Binding antibodies to pegfilgrastim were occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of detected using a BIAcore assay. The approximate limit of initial anti-allergic treatment. Permanently discontinue Neulasta detection for this assay is 500 ng/mL. Pre-existing binding in patients with serious allergic reactions. Do not administer antibodies were detected in approximately 6% (51/849) Neulasta to patients with a history of serious allergic reactions of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline to pegfilgrastim or filgrastim. developed binding antibodies to pegfilgrastim following Allergies to Acrylics treatment. None of these 4 patients had evidence of The On-body Injector for Neulasta uses acrylic adhesive. neutralizing antibodies detected using a cell-based bioassay. For patients who have reactions to acrylic adhesives, The detection of antibody formation is highly dependent on use of this product may result in a significant reaction. the sensitivity and specificity of the assay, and the observed Use in Patients With Sickle Cell Disorders incidence of antibody positivity in an assay may be influenced Severe sickle cell crises can occur in patients with sickle cell by several factors, including assay methodology, sample disorders receiving Neulasta. Severe and sometimes fatal sickle handling, timing of sample collection, concomitant medications, cell crises can occur in patients with sickle cell disorders and underlying disease. For these reasons, comparison of receiving filgrastim, the parent compound of pegfilgrastim. the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Potential for Tumor Growth Stimulatory Effects on Malignant Cells Postmarketing Experience The granulocyte-colony stimulating factor (G-CSF) receptor The following adverse reactions have been identified during through which pegfilgrastim and filgrastim act has been found post approval use of Neulasta. Because these reactions are on tumor cell lines. The possibility that pegfilgrastim acts reported voluntarily from a population of uncertain size, it is not as a growth factor for any tumor type, including myeloid always possible to reliably estimate their frequency or establish malignancies and myelodysplasia, diseases for which a causal relationship to drug exposure. Decisions to include pegfilgrastim is not approved, cannot be excluded. these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) ADVERSE REACTIONS reported frequency of the reaction, or (3) strength of causal The following serious adverse reactions are discussed in relationship to Neulasta. greater detail in other sections of the Brief Summary: Gastro-intestinal disorders:: Splenic rupture [see Warnings • Splenic Rupture [See Warnings and Precautions] and Precautions] • Acute Respiratory Distress Syndrome [See Warnings Blood and lymphatic system disorder:: Sickle cell crisis and Precautions] [see Warnings and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Hypersensitivity reactions:: Allergic reactions/hypersensitivity, • Use in Patients with Sickle Cell Disorders [See Warnings including anaphylaxis, skin rash, and urticaria, generalized and Precautions] erythema and flushing [see Warnings and Precautions] • Potential for Tumor Growth Stimulatory Effects on Malignant Respiratory, thoracic, and mediastinal disorder:: ARDS Cells [See Warnings and Precautions] [see Warnings and Precautions] The most common adverse reactions occurring in ≥ 5% of General disorders and administration site conditions: patients and with a between-group difference of ≥ 5% higher Injection site reactions in the pegfilgrastim arm in placebo controlled clinical trials Skin and subcutaneous tissue disorders:: Sweet’s syndrome, are bone pain and pain in extremity. Cutaneous vasculitis Clinical Trials Experience Because clinical trials are conducted under widely varying DRUG INTERACTIONS conditions, adverse reaction rates observed in the clinical trials No formal drug interaction studies between Neulasta and other of a drug cannot be directly compared with rates in the clinical drugs have been performed. Increased hematopoietic activity trials of another drug and may not reflect the rates observed in of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider clinical practice. these findings when interpreting bone-imaging results. Neulasta clinical trials safety data are based upon 932 patients USE IN SPECIFIC POPULATIONS receiving Neulasta in seven randomized clinical trials. The Pregnancy population was 21 to 88 years of age and 92% female. The Pregnancy Category C ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose received a single 100 mcg/kg (n = 259) or a single 6 mg (based on body surface area). Signs of maternal toxicity (n = 546) dose per chemotherapy cycle over 4 cycles. occurred at these doses. Neulasta should be used during

Decreasing Readmissions through Opportunities Provided (DROP), which aims to reduce by 20% the annual rate of readmissions within 30 days of bariatric surgery. One in every 20 patients who undergoes bariatric surgery in the United States is readmitted to the hospital within 30 days, according to an analysis of 18,296 bariatric procedures carried out in 2012 and presented at the 2014 Clinical

pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Neulasta is administered subcutaneously via a single prefilled syringe for manual use or for use with the On-body Injector for Neulasta which is co-packaged with a single prefilled syringe. For manual use or On-body Injector for Neulasta use, visually inspect parenteral drug products (prefilled syringe) for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. The needle cap on the prefilled syringes contains dry natural rubber (derived from latex); persons with latex allergies should not administer these products. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegﬁlgrastim) Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799 © 2015 Amgen Inc. All rights reserved. www.neulastaHCP.com, 1-800-77-AMGEN (1-800-772-6436) v 14.0

71678-R2-V1

Congress of the American College of Surgeons (abstract SP01), in San Francisco. When investigators looked more closely at those readmissions, they found many could have been avoided by dietary counseling and filling prescriptions before hospital discharge. Based on that analysis, Dr. Luka and his colleagues put together a guideline for health care providers’ discussions with patients about medications. They also made a patient information video that highlights the need for diligent medication reconciliation.

Polypharmacy a Problem Before undergoing surgery, patients typically are taking a significant number of medications to manage their comorbidities. After surgery, those medication requirements often change and drop dramatically, with one recent study presented at the bariatric meeting (abstract 103) showing use of diabetes drugs fell 73.7% after surgery and cardiac medications decreased by 47%. Pharmacists need to be involved in medication management and counseling, Dr. Luka noted. “When we look at nationwide data, 3% to 5% of all emergency department visits are adverse drug–related,” he said. “Those are the kind of things that we are trying to prevent with better education.” Closing that education gap is “a role that pharmacists can fill,” Dr. Luka said. “I see that there needs to be much more involvement by pharmacists communicating with patients and with outpatient services. We need a communication plan that includes hospital pharmacists, community pharmacists, primary care providers, surgeons and patients.” He stressed that pharmacists have a unique role in relaying complex medication information to those who lack the depth of knowledge. “When we give a portion of that role to the pharmacist, we allow for a focused and individualized educational session to tailor medication therapy across different patient populations. Pharmacists may be able to enhance patient throughput by providing the added benefit of tailoring medication therapy” to the patient. DROP requires pharmacists, or nurse practitioners working with hospital pharmacists, to meet with patients pre- and postoperatively to review their medications, he pointed out. Pharmacists

Clinical 23

Pharmacy Practice News • May 2015

Hospital Readmissions or nurse practitioners counsel patients about use of β-blockers at the time of surgery, management of antihypertensives, and discuss any medications for pain, post-transplant, anticoagulation, diabetes and mood disorders. DROP organizers identified patients considered at high risk for readmission. The list includes those with a body mass index greater than 50 kg/m2 (30.2% vs. 24.6% for patients who were not readmitted; P<0.001); longer operating times (115 vs. 132 minutes; P<0.001), index length of stay longer than four days (9.57% vs. 3.36%; P<0.001) and a preoperative diagnosis of diabetes (31.1% vs. 27.7; P<0.02). “What’s helpful about that is for patients at a higher risk for readmission, we escalate coordination of care early

Bill Proposes Changing CMS Readmissions Penalties

‘Pharmacists may be able to enhance patient throughput by providing the added benefit of tailoring medication therapy [on an individual patient basis.]’ —Bishoy Luka, PharmD, BCNSP on,” said John Morton, MD, the president of the American Society for Metabolic and Bariatric Surgery and director of bariatric surgery, Stanford University School

of Medicine, Stanford, Calif. “We can decrease readmissions with a lot of commonsense things that can be done at the right time for the right patient.”

NOW APPROVED

esearchers who looked at readmission rates for acute myocardial infarction, congestive heart failure and pneumonia in 4,000 hospitals found that nearly 60% of the variation in hospital readmission rates was due to factors beyond the control of hospital staff, such as community attributes including unemployment rates, never-married residents and fewer general practitioners per capita (Health Services Research 2015 Feb. [Epub ahead of print]). Yet, the Centers for Medicare & Medicaid Services (CMS) penalizes hospitals for an excessive number of readmissions for certain conditions. Hospitals in low-income neighborhoods have higher readmissions scores, and therefore, receive lower reimbursements, than hospitals in middle-class or wealthy neighborhoods, according to the American Hospital Association (AHA). The AHA urged Congress to support the Establishing Beneficiary Equity in the Hospital Readmission Program bill (Act, S. 688/H.R. 134), which would require CMS to account for patient sociodemographic status when making risk adjustments to the readmissions penalties. At a briefing on Capitol Hill, the AHA also released a new TrendWatch Report showing that overall the national readmission rate fell to 17.5% in 2013, after holding steady at around 19.5% for many years. However, certain populations are more likely to be readmitted. Medicare beneficiaries with multiple chronic conditions have higher readmission rates (9% if they have one condition and 25% if they have six or more).

In February, the DROP program was rolled out at about 100 randomly selected bariatric surgery centers in the United States. It will be evaluated over a 12-month period before a final version is extended to all MBSAQIP centers. DROP was piloted in 2008 by Stanford’s Bariatric Surgery Department, where it reduced bariatric surgery readmissions by 75% by implementing changes in patient education, discharge planning, and pre- and postoperative checklists.

AVAILABLE SOON

—Christina Frangou

24 Clinical

Pharmacy Practice News • May 2015

Critical Care

Multiple IV Lines Pose Safety Issues Annapolis, Md.—The most common errors associated with multiple IV infusions occur during setup and include infusion rate or line mix-ups, IV lines not attached to patients and errors associated with piggyback infusions, according to a recent study of more than 900 IV line errors reported to the Pennsylvania Patient Safety Authority. There are a number of risk reduction strategies for these errors, including labeling IV lines and setting up infusions completely and one at a time, said the study’s co-author, Matthew Grissinger, RPh, FASCP, the director of Error Reporting Programs at the Institute for Safe Medication Practices (ISMP). Mr. Grissinger presented the results of the study—and strategies for implementing the safety lessons learned—during a kick-off meeting in March for the National Coalition for Infusion Therapy Safety, an initiative by the Association for the Advancement of Medical Instrumentation (AAMI) Foundation and industry partners. The group’s goal is to develop and promote solutions that improve infusion therapy–related patient outcomes. The ISMP study found high-alert

medications were involved in 71% (n=644) of all multiple IV infusion errors, most often heparin. Forty-eight percent of incidents (n=436) were categorized as harm score D or greater, and 6.2% (n=56) as harm score E or greater, as defined by the National Coordinating Council for Medication Error Reporting and Prevention. And 95% of errors (n=867) reached the patient. The study stemmed from observations that ISMP made as a subcontractor for the ECRI Institute, a Plymouth, Pa.based nonprofit group that applies scientific research to patient safety and other health care issues. In reviewing medication errors in the mandatory state hospital medical error reporting program for all hospitals in Pennsylvania, ISMP found that “over time, people’s IV lines were mixed up,” Mr. Grissinger said. “Patients were getting these IV fluids that would normally go 80 to 100 mL per hour but were only going 10 mL per hour. Then dangerous drugs like heparin infusions, which should only go about 10 mL per hour, were running 100 mL per hour.” Mr. Grissinger and his colleague Amanda Wollitz, PharmD, a patient safety

analyst, reviewed 907 medication error reports submitted from June 2004 to August 2013. The most frequent error was rate of infusion mix-up or line mix-up among two or more medications (22.6%, or 205 errors). High-alert medications, most frequently heparin, were involved in 92% (79) of IV line mix-ups. The most frequently interchanged IV rates were heparin with IV hydration, parenteral nutrition with intralipids, and insulin with IV hydration. IV lines not being attached to patients was another common problem, representing 14.6%, or 132 errors. The top three medications involved were heparin, morphine and insulin. Multiple reports noted that these errors resulted in adverse patient events. “They would be infusing, but they would be running on the floor,” Mr. Grissinger said. “It’s pretty amazing.” Sometimes people only worry about overdoses, he noted, but “the impact of not getting [enough] medication and/or getting too much are both bad. With these types of medications, if you don’t get enough of them, that’s a whole other set of consequences you have to worry about.” The third most common problem seen

Making Smart IV Pumps (a Bit) Smarter

bundle of interventions may be moderately effective in reducing hospitals’ overall rate of smart pump–related errors and the rate of serious IV medication errors, according to early results of a study completed at 10 U.S. hospitals. Implementing the interventions, in the areas of medication labeling and tubing, unauthorized medications and smart pump and drug library use, led to a modest decline in overall IV medication errors, from 1,402 in early-mid 2013 to 1,296 in late 2014 (P<0.001), said study director David Bates, MD, MSc, the senior vice president and chief innovation officer for Brigham and Women’s Hospital in Boston. The number of serious medication errors declined from 359 in early-mid 2013 to 307 in late 2014 (P=0.001), according to the research, which was funded by AAMI and the CareFusion Foundation. These are preliminary results; final results are still being tabulated to submit for publication. “The overall conclusion was that the intervention did work, that is to say error rates fell modestly, but there is still substantial room for improvement,” Dr. Bates told Pharmacy Practice News. It would help to have electronic communication between smart pumps and electronic medical records, he said, which very few hospital have, and there were many issues surrounding overfill. “Often a bag that is supposed to be a 500-mL bag will have more fluid in it than that,” he said. “There are no good approaches for handling that. The pumps really struggle when that bag is overfilled.” For the study, which was conducted in medical and surgical units, and medical and surgical ICUs at three community hospitals and seven academic medical centers, researchers measured the rates and types of smart pump– related medication errors, then implemented a series of

interventions, and remeasured medication errors. The most frequent errors noted were labeling errors; tubing not being tagged according to institution policy; fluids or medication being administered with no order in the medical record; and not using the smart pump decision support. The interventions included a standardized labeling toolkit compliant with Joint Commission standards; standardized IV tubing change labels; a standardized discontinuation policy; standardized keep vein open (KVO) rates and order sets; standardized verbal orders; a medication barcode scanning compliance rate report; a drug library use compliance report; and a standardized drug library list. Hospitals implemented as many of the interventions as they could. The hospitals also used different smart pump vendors. The areas the study interventions focused on “do identify some opportunities” for all hospitals, Dr. Bates pointed out. Every hospital should pay attention to its drug libraries, and use data that come from their pumps as an indicator of drug library compliance, he noted. “They should also be thinking of how to handle issues like discontinuation, and it would help most hospitals to have a standardized KVO rate—there’s a remarkable amount of disagreement about that.” Labeling also continues to be an issue, Dr. Bates said: “The best long-term approach is to have as much of the labeling done as possible through standardized printing and not require providers to have to do a lot of additional things.” —K.B. Dr. Bates is on the board of SEA Medical Systems, Inc., which makes IV pump technology.

were errors associated with piggyback infusions, making up 12.8%, or 116 errors, again with heparin the most common medication involved. Issues included secondary IV lines being attached below the pump, clamps remaining closed or incorrect pump programming. Of all reported events, 11% (n=101) involved patients younger than 18 years. Heparin was the high-alert medication most frequently involved in errors (16% of errors; n=151), followed by insulin (7.6% of errors; n=69) and parenteral nutrition (5.2% of errors; n=47). ICUs ranked highest among units where IV line errors were reported (30%; n=274), followed by medical-surgical units (14%; n=128) and telemetry units (6.6%; n=60), according to the study, which was first published in the Pennsylvania Patient Safety Advisory journal (2014;11[1]:1-6). Mr. Grissinger offered a number of risk reduction strategies: • Set up infusions completely, and one at a time. If a patient is on five IVs, start with the first one and set up the entire process from start to finish before starting a second IV. “It sounds simple, but if you get interrupted halfway through or don’t do it in sequence, you can imagine the mix-ups that can occur,” he said. • Administer high-alert medications as primary infusions. Do not connect them to anything except the patient, and do not connect any other infusions to them. • Restrict pump operation to qualified, credentialed personnel. • Place IV pumps and epidural pumps on opposite sides of patient beds to reduce the risk for line mix-ups. • Raise awareness of IV medication errors among your staff. Even these recommendations rely on people remembering to intervene, Mr. Grissinger said: “That’s not always a good strategy. “Nurses have a lot of things going on—a lot of distractions, a lot of patients, etc. We always encourage people to label their IV lines in at least two locations, so maybe on the IV line where it connects to the patient and then somewhere up toward the infusion pump so that when you string it through you can see the name of the drug on the label. It helps double check and match things up.” —Karen Blum None of the sources reported any relevant ﬁnancial conﬂicts of interest.

Clinical 25

Pharmacy Practice News • May 2015

Critical Care

FEEDING GAP continued from page 1

calculate optimal feeding and diagnose malnutrition, among other relatively simple strategies that could help sick children and enhance bottom lines. “Feeding is [not enough of a priority] in the intensive care units,” said Nilesh Mehta, MD, an associate professor of anesthesia at Harvard Medical School, Boston, and the director of critical care nutrition at Boston Children’s Hospital. “People have long focused their attention on other complex and expensive therapies but often ignore the importance of providing basic nutrition.” Although malnutrition concerns are increasingly recognized for adults, children may be the most vulnerable to the unintentional neglect. “Critically ill children bring another level of complexity,” said Carol Rollins, MS, RD, PharmD, a coordinator for the nutrition support team at the University of Arizona Medical Center, Tucson. With lower energy reserves, she noted, children can fall into a starvation state quicker than adults. She also highlighted a child’s growth as a critical consideration. “We know that for a neonate or infant, a malnourished brain may not meet its full potential,” Dr. Rollins said. Several years ago, when Dr. Mehta and his colleagues noticed the stark heterogeneity in feeding practices for critically ill children at their hospital, they decided

No malnutrition

to take action. “Everyone was doing what they thought was best, but there was no uniform strategy employed,” Dr. Mehta said. “Also, there wasn’t much evidence to guide nutrition practices at the bedside.” He led an interdisciplinary group of dietitians, gastroenterologists, pharmacists, critical care physicians and nurses to develop a feeding algorithm. Today, that algorithm provides stepwise guidance for initiating and advancing the delivery of nutrients in critically ill children at hospitals worldwide. A paper his team published last year showed the algorithm improved delivery of energy and protein, resulted in fewer unintended feeding interruptions and decreased use of

Malnutrition

350

300

P i Patients, n

250

200

150 n=110

100

parenteral nutrition ((Pediatr Crit Care Med 2014;15[7]:583-589). In their latest study, presented at A.S.P.E.N. (abstract 14), Dr. Mehta and his team described nutrition delivery and clinical outcomes for 1,245 children requiring mechanical ventilation from 59 pediatric ICUs (PICUs) across 15 countries. Interruptions in feeding and shortages in both daily energy and protein were common throughout the international cohort. The majority of patients (985; 79%) received enteral nutrition. Among these children, 74% had their feeding interrupted for an average of eight hours a day. Overall, patients received far less energy and protein than prescribed: 36% and 47%, respectively. “We are uniformly bad at delivering protein to critically ill children,” Dr. Mehta said. The shortfall appeared to predict poor outcomes. After adjusting for the severity of a child’s illness, mortality was significantly associated with insufficient enteral protein intake, independent of energy intake (P ( <0.001). An increase in protein adequacy—from less than 20% to more than 60%—led to a significant drop in 60-day mortality (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.16-0.65). Once again, knowledge can be power. Based on their findings, the team highlighted “modifiable factors” that could improve protein delivery, including early initiation of enteral nutrition, use of post-pyloric enteral route, decreased interruptions and the presence of a dedicated dietitian.

Monitoring Malnutrition 50 n=7

Old Method

MTool

Figure. Malnutrition identification by method.

Of course, malnutrition must first be recognized before it can be addressed. The University of Michigan C.S. Mott Children’s Hospital’s MTool provides an innovative approach. In developing their standardized tool to diagnose pediatric malnutrition—its first iteration dating back to 2013—researchers examined the relevant

scientific literature. In particular, said Kate Ludwig, MPH, RD, CSP, a pediatric clinical dietitian at the hospital, they referenced an article by Dr. Mehta ((J Parenter Enteral Nutr 2013;37[4]:460-481) that describes a paradigm shift toward an etiology-based definition of pediatric malnutrition endorsed by A.S.P.E.N, the Academy of Nutrition and Dietetics and the American Academy of Pediatrics. Height, weight, weight for length and body mass index and z-scores are used in the first step of the process as indicators to alert practitioners of a potential problem, Ms. Ludwig explained. The team then performs a thorough nutritional assessment to determine the etiology of malnutrition: Is a medical condition, dietary intake, socioeconomic status or inflammation playing a role? In the study presented at A.S.P.E.N. (abstract 28), Ms. Ludwig used the MTool to look retrospectively at 327 children who were admitted to and stayed for at least four days in her institution’s PICUs between Jan. 1 and Dec. 31, 2012.

‘We are uniformly bad at delivering protein to critically ill children.’ —Nilesh Mehta, MD Before applying the MTool, 2% of patients were diagnosed with malnutrition. Once the tool was applied, that number jumped to 34%. MTool characterized 26% of those patients as having severe malnutrition. The highest rates of malnutrition were among children with respiratory and neurologic diagnoses. Ms. Ludwig further determined that children identified by the tool as malnourished fared worse than those not flagged. The patients diagnosed with malnutrition had significantly higher incidence of death (10% vs. 4%; P=0.046). Although not statistically significant, these children also spent 1.2 days longer on a ventilator ((P=0.315) and stayed an average of 2.3 days longer ( =0.302) in the hospital compared with (P nonmalnourished children. “Unfortunately, because it was retrospective, we weren’t able to act on anything,” Ms. Ludwig said. However, today, she added, her hospital is able to apply MTool to identify at-risk patients earlier and, therefore, intervene sooner to improve outcomes. MTool is currently available for purchase through the University of Michigan Mott Children’s Hospital Patient Food and Nutrition Services website. Ms. Ludwig noted that they’ve received requests from all over the United States, with distribution to more than 200 institutions shortly after it became available. see FEEDING GAP, page 30

26 Clinical

Pharmacy Practice News • May 2015

Bleeding Management

ISMP Urges Caution With New Oral Anticoagulants T

he new oral anticoagulants introduced over the past several years are touted for being safer and requiring less monitoring than warfarin, but experts are urging clinicians to study the intricacies of administering these agents. “Dosing these agents can get pretty complicated,” Matthew Fricker, MS, RPh, the program director at the Institute for Safe Medication Practices (ISMP), in Horsham, Pa., said during a recent ISMP webinar. “For example, not only do dosing recommendations differ by indication, there are loading and maintenance doses, which can confuse some patients.” Indeed, a lack of clarity surrounding rivaroxaban’s (Xarelto, Bayer/Janssen) dosing regimen for venous thromboembolism (VTE) treatment (it should be administered at 15 mg twice daily for 21 days and 20 mg once daily thereafter) may have been why one patient receiving the drug for this indication selfadministered 50 mg daily of the drug ((ISMP Acute Care Medication Safety Alert! 2014;19[19]). “The patient took both the loading dose and the maintenance dose together, probably because both prescriptions

were filled at the same time,” said Mr. Fricker, emphasizing the importance of patient education at discharge.

Renal Function a New Consideration

‘The problem is that we don’t know how safe and effective PCCs are in the context of the new oral anticoagulants.’ —Michael Gulseth, PharmD

Table. Dosing Adjustments for the Newer Anticoagulants Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Stroke prophylaxis with non-valvular atrial fibrillation

150 mg bid

20 mg daily

5 mg bid

60 mg once daily if CrCl 50-95 mL/min

Renal adjustment

75 mg bid if CrCl 15-30 mL/min; no dosing recommendations if CrCl <15 mL/min

15 mg daily if CrCl 15-50 mL/min; avoid use if CrCl <15 mL/min

2.5 mg bid if SrCr ≥1.5 mg/dL and at least one of these characteristics present: age ≥80 y and ≤60 kg

Do not use if CrCl >95 mL/min; 30 mg once daily if CrCl 15-50 mL/min

VTE

150 mg bid (after parenteral therapy)

15 mg bid for 21 d, then 20 mg daily for 6 mo

10 mg bid for 7 d, then 5 mg bid

Following parenteral therapy, 60 mg once daily when weight is >60 kg; 30 mg once daily if ≤60 kg

Renal adjustment

No dosage recommendations if CrCl ≤30 mL/min

Avoid use if CrCl <30 mL/min

No adjustment required

30 mg once daily if CrCl ≤15-50 mL/min

Long-term VTE prophylaxis

150 mg bid

20 mg daily

2.5 mg bid

Not approved for this indication

Renal adjustment

No dosage recommendations for CrCl <30 mL/min

Do not use if CrCl <30 mL/min

No adjustment required

VTE prophylaxis in patients undergoing orthopedic surgery

Not approved

For knee replacement: 10 mg daily for 12 d; For hip replacement: 10 mg daily for 35 d

2.5 mg bid

Do not use if CrCl <30 mL/min

No adjustment required

Renal adjustment

b d, tw bid, twice ce daily; da y; CrCl, C C , creatinine c eat ec clearance; ea a ce; SrCr, S C , serum se u creatinine; c eat e; VTE, V , ve venous ous thromboembolism t o boe bo s

Not approved

The dosing formula is made more complex as renal function enters the equation, Michael Gulseth, PharmD, the program director for anticoagulation services at Sanford USD Medical Center in Sioux Falls, S.D., said during the ISMP webinar. “This is something practitioners are not used to thinking about with warfarin,” he explained. Manufacturers of two of the four new oral anticoagulants recommend that non-valvular atrial fibrillation patients who are given their medications for stroke prophylaxis undergo dosing adjustments, while the other two agents either have no recommendations when renal function is poor, or recommend against using the drug altogether for this indication, Dr. Gulseth pointed out. Additionally, for the treatment or long-term prophylaxis of VTE, there are no indications for dabigatran (Pradaxa, Boehringer Ingelheim) in patients with creatinine clearance (CrCl) less than 30 mL/min, and rivaroxaban is not recommended for use in patients with this level of renal impairment, he noted. When dabigatran is used, declining renal function is accompanied by an increase in the risk for extracranial bleeding that is greater than the rise in bleeding risk with warfarin, Dr. Gulseth warned (Circulation 2014;129[9]:961-970). Pharmacists and many providers are accustomed to considering renal function when prescribing a variety of medications, but Dr. Gulseth said a “completely unique situation” exists with edoxaban (Savaysa, Daiichi Sankyo): normal renal function (CrCl >95 mL/min) precludes use of the drug for stroke prophylaxis in non-valvular atrial fibrillation. (The drug’s boxed warning indicates that in individuals with CrCl >95 mL/min, the risk for ischemic stroke with the 60-mg dose is significantly greater than with warfarin. Therefore, the drug shouldn’t be used in patients with CrCl >95 mL/min, according to the manufacturer.) “Getting providers and pharmacists to think about good renal function as a safety concern is definitely a challenge,” Dr. Gulseth added.

Reversal Agents a Thorny Issue Arguably the most significant clinical controversy surrounding use of the new oral anticoagulants is the lack of direct reversal agents, Dr. Gulseth asserted. see ANTICOAGULANTS, page 29

Give your patients the relief they need Betamethasone Sodium Phosphate & Betamethasone Acetate* Injectable Suspension, USP Product Name Betamethasone Sodium Phosphate & Betamethasone Acetate* Injectable Suspension, USP

Fast-Acting

Long-Lasting

3 3 3

Kenalog®

Depo-Medrol®

(Triamcinolone Acetonide) Injectable Suspension, USP

(Methylprednisolone Acetate Injectable Suspension, USP)

Kenalog® is a registered trademark of Bristol-Myers Squibb. Depo-Medrol® is a registered trademark of Pfizer Inc.

*Betamethasone 6 mg/mL as 3 mg/mL Betamethasone Sodium Phosphate and 3 mg/mL Betamethasone Acetate The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. Important Safety Information: Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. As with any potent corticosteroid, adverse events have been associated with Betamethasone Sodium Phosphate and Betamethasone Acetate, Injectable Suspension, USP including fluid and electrolyte disturbances, as well as adverse reactions involving the following systems: allergic reactions, cardiovascular, dermatologic, endocrine, gastrointestinal, metabolic, musculoskeletal, neurological/ psychiatric, ophthalmic and other. Corticosteroids may also affect immune response. Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. Betamethasone Sodium Phosphate and Betamethasone Acetate, Injectable Suspension, USP should not be administered intravenously or used in systemic fungal infections. Vaccination administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infections. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles and to seek medical advice without delay if exposed.

Please see Brief Summary for Full Prescribing Information on next page

Dual-Agent

FAST-ACTING

LONG-LASTING ®

www.DualAgentBeta.com

Cortic osteroid BB036 Rev. 4/2015

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP 6 mg per mL

Rx only DESCRIPTION Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP is a sterile aqueous suspension containing betamethasone 3 mg per milliliter as betamethasone sodium phosphate, and betamethasone acetate 3 mg per milliliter. Inactive ingredients per mL: dibasic sodium phosphate 7.1 mg; monobasic sodium phosphate 3.4 mg; edetate disodium 0.1 mg; and benzalkonium chloride 0.2 mg as a preservative. The pH is adjusted to between 6.8 and 7.2. INDICATIONS AND USAGE When oral therapy is not feasible, the intramuscular use of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as follows: Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions. Dermatologic Diseases Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome). Endocrine Disorders Congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis. Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance. Gastrointestinal Diseases To tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis. Hematologic Disorders Acquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia. Miscellaneous Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy. Neoplastic Diseases For palliative management of leukemias and lymphomas. Nervous System Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy. Ophthalmic Diseases Sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Renal Diseases To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus. Respiratory Diseases Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus. The intra-articular or soft tissue administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis. The intralesional administration of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum. Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, may also be useful in cystic tumors of an aponeurosis or tendon (ganglia). CONTRAINDICATIONS Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is contraindicated in patients who are hypersensitive to any components of this product. Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. WARNINGS Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension should not be administered intravenously. Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use. General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. In patients on corticosteroid therapy subjected to any unusual stress, hydrocortisone or cortisone is the drug of choice as a supplement during and after the event. Cardio-renal Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Infections General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B Injection and Potassium-Depleting Agents section). Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroidinduced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. Corticosteroids should not be used in cerebral malaria. Tuberculosis The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted Viral Infections Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. If exposed to chickenpox, prophylaxis with varicella zosterr immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered. Neurologic Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Gastrointestinal and Neurologic/ Psychiatric sections). High doses of corticosteroids, including Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, should not be used for the treatment of traumatic brain injury. Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex. PRECAUTIONS General This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual. Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement. Cardio-renal As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency. Endocrine Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy. Therefore, in any situation of stress occurring during that period, naturally occurring glucocorticoids (hydrocortisone cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocorticoal deficiency states. Gastrointestinal Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent. There is an enhanced effect of corticosteroids in patients with cirrhosis. Intra-Articular and Soft Tissue Administration Intra-articular injected corticosteroids may be systematically absorbed. Appropriate examination of any joint fluid present is necessary to exclude a septic process. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted. Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously injected joint is not usually recommended. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS, Musculoskeletal section). Musculoskeletal Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (ie, decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (ie, postmenopausal women) before initiating corticosteroid therapy.

Neuro-psychiatric Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION). An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (eg, myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (eg, pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Ophthalmic Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored. Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection. Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Drug Interactions Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B Injection and Potassium-Depleting Agents When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. Anticoagulants, Oral Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect. Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular Drugs Serum concentrations of isoniazid may be decreased. Cholestyramine Cholestyramine may increase the clearance of corticosteroids. Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis Glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, Including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Hepatic Enzyme Inducers (eg, barbiturates, phenytoin, carbamazepine, rifampin) Drugs which induce hepatic microsomal drug-metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased. Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased riskk of corticosteroid side effects. Nonsteroidal Anti-inflammatory Agents (NSAIDS) Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin Tests Corticosteroids may suppress reactions to skin tests. accines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Route administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination section). Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis. Steroids may increase or decrease motility and number of spermatozoa in some patients. Pregnancy Teratogenic Effects Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Nursing Mothers Systematically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, eg, severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations. The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systematically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (ie, cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose. Geriatric Use No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and young patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS (listed alphabetically, under each subsection) Allergic Reactions Anaphylactoid reaction, anaphylaxis, angioedema. Cardiovascular Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine Decreased carbohydrate and glucose tolerance, development of cushingoid state, glucosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and Electrolyte Disturbances Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention. Gastrointestinal Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis. Metabolic Negative nitrogen balance due to protein catabolism. Musculoskeletal Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic section). Ophthalmic Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. OVERDOSAGE Treatment of acute overdose is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced. DOSAGE AND ADMINISTRATION Benzyl alcohol as a preservative has been associated with a fatal “Gasping Syndrome” in premature infants and infants of low birth weight. Solutions used for further dilution of this product should be preservative-free when used in the neonate, especially the premature infant. The initial dosage of parenterally administered Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension may vary from 0.25 to 9.0 mg per day depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. It Should Be Emphasized That Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

SEE FULL PRESCRIBING INFORMATION FOR FULL DOSAGE AND ADMINISTRATION DIRECTIONS. BS1019 Revised July 2014 ®

Clinical 29

Pharmacy Practice News • May 2015

Bleeding Management

ANTICOAGULANTS continued from page 26

Bereft of these agents, clinicians have been turning to off-label use of nonactivated and activated prothrombin complex concentrates (PCCs), such as Kcentra (CSL Behring) and factor VIII inhibitor bypassing activity (FEIBA NF; Baxter Healthcare). “The problem is that we don’t know how safe and effective PCCs are in the context of the new oral anticoagulants,” said Dr. Gulseth (see sidebar for reversal agents in the pipeline). That clinical haziness along with the risk for thromboembolic events when PCCs are used in individuals with a history of such events calls for clinicians to reserve PCCs for lifethreatening situations, or when bleeding requires immediate control or if

an emergency invasive procedure is needed, Dr. Gulseth said. “Otherwise, for many other bleeding situations, hemodynamic support with blood and fluids will be the appropriate treatment, since these are reversible inhibitors with relatively short halflives,” he said.

Order Sets Help Ensure Accuracy Dr. Gulseth’s colleague, Rhonda Hammerquist, PharmD, a medication safety officer at Sanford USD Medical Center, told webinar attendees that the center has developed order sets and is in the process of implementing hard stops during provider prescribing to help ensure the new oral anticoagulants are dosed accurately. “We created detailed diseasespecific order sets for the new agents with instructions on dose transitions and

titration and on renal function considerations,” Dr. Hammerquist explained. “We’re also working to require prescribers to enter an indication when ordering the oral anticoagulants, so that the pharmacist can easily verify the dosing is correct.” She said that, despite the paucity of data on use of PCCs as reversal agents for the new oral anticoagulants, her colleagues have also created order sets for PCC use. “Our safety officers and the medication safety committee decided that doing something was better than doing nothing.” The absence of clear data on the safety and efficacy of PCCs for reversal of bleeding with the new oral agents makes issuing recommendations “controversial,” Dr. Gulseth said, but he believes that “in the heat of the moment, a provider needs guidance on

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ew data suggest that direct acting oral anticoagulants could become the standard of care for post-cardioversion prophylaxis. To access, scan the 2D barcode.

what to do, and it is better to standardize that guidance.” —David Wild Dr. Gulseth reported serving as a consultant and speaker for Bristol-Myers Squibb, Janssen and Pfizer and as a consultant for Boehringer-Ingelheim, Daiichi Sankyo and Portola. Dr. Hammerquist and Mr. Fricker reported no relevant financial conflicts of interest.

Three New Oral Anticoagulant Reversal Agents on the Horizon

hree novel drugs have demonstrated their efficacy as reversal agents in healthy individuals receiving the direct oral anticoagulants (DOACs), and one has already been granted priority review as a reversal agent for dabigatran. “If they prove to be effective, I think these antidotes will not only offer a useful treatment strategy for patients who have major bleeding on one of the DOACs, but also further increase the acceptance and use of the new oral anticoagulants,” said Stephan Moll, MD, a professor of medicine at the University of North Carolina School of Medicine in Chapel Hill, and a cofounder of ClotConnect.org, an information and outreach program developed by the school to promote best practices in bleeding disorders management.

Andexanet alfa This recombinant protein (Portola Pharmaceuticals) reverses anti–factor Xa activity and has received orphan drug and breakthrough therapy designations by the FDA, potentially placing it on an expedited and simplified marketing approval pathway. In a Phase II, randomized, placebo-controlled trial presented at the American Society of Hematology (ASH) 2014 annual meeting (abstract 4269), 17 healthy individuals received edoxaban (Savaysa, Daiichi Sankyo) 60 mg for six days. Andexanet alfa was administered three hours after the last edoxaban dose as a 600 or 800 mg bolus with a subsequent one-hour infusion of 8 mg per minute. Anti–factor Xa activity fell by 52% and 73% in the 600 and 800 mg groups, respectively, immediately after each bolus, and returned to preedoxaban levels within approximately two hours of bolus administration. Andexanet alfa was also studied as a reversal agent for rivaroxaban (Xarelto, Janssen Pharmaceutica/Bayer) in the ANNEXA-R trial (ClinicalTrials. gov identifier: NCT02220725). Partial findings presented at the American College of Cardiology 2015 annual meeting (abstract 912-08) showed efficacy in 41 indiviudals who received rivaroxaban 20 mg once daily for four days followed by an 800 mg IV bolus of andexanet alfa or placebo. Within 10 minutes, 26 of 27 andexanet alfa recipients (96%) experienced a 90% or greater reduction in anti–factor Xa activity relative to peak rivaroxaban exposure. The agent is also being studied as a reversal agent for apixaban (ClinicalTrials.gov identifier: NCT02207725) and in patients receiving a factor Xa

i hibit who inhibitor h are experiencing i i an acute t major j bleed bl d (ClinicalTrials.gov identifier: NCT02329327).

Aripazine Aripazine (Perosphere) is a synthetic small molecule with broad activity against several established and new oral anticoagulants. In a double-blind, placebo-controlled study, 80 healthy individuals received edoxaban in a single IV dose of 5 to 300 mg, either alone or after an oral dose of edoxaban 60 mg (N Engl J Med 2014;371[22]:2141-2142). Three hours after IV edoxaban administration, the individuals were given aripazine in a single IV dose of 100 to 300 mg. Whole-blood clotting time returned to within 10% of normal by 10 to 30 minutes after aripazine administration and remained stable for 24 hours, the findings showed. However, “there are presently no ongoing clinical studies listed on ClinicalTrials.gov, questioning whether the development of aripazine is further progressing,” Dr. Moll said.

Idarucizumab Idarucizumab (Boehringer Ingelheim) is a monoclonal antibody against dabigatran for use in patients who require rapid reversal of the anticoagulant action of dabigatran. The FDA granted priority review, and if approved, we be given a breaktrhough therapy designation.

Results R lt ffrom a randomized, double-blind, placebocontrolled, crossover study of 46 healthy or renally impaired individuals, aged 45 to 80 years, were presented at the ASH 2014 annual meeting (abstract 344). Participants with or without renal impairment received dabigatran 150 and 220 mg, respectively, twice daily for three days, as well as a single dose on the fourth day. Two hours after the last dose, individuals with normal kidney function received idarucizumab 5 g in a single five-minute infusion, while renally impaired patirents each received two fiveminute infusions of 2.5 g. Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation. Additionally, some healthy subjects received dabigatran 24 hours after idarucizumab infusion and had anticoagulation restored, and some of these individuals subsequently received idarucizumab again, with successful reversal of anticoagulation. Idarucizumab administration was associated with a dose-related increase in urinary protein levels and no clinically relevant adverse events. A Phase III clinical trial is examining the agent’s capacity to reverse anticoagulation in dabigatrantreated patients who have uncontrolled bleeding or who require emergency surgery or procedures (ClinicalTrials.gov identifier: NCT02104947). —D.W. Dr. Moll reported a consultantship with Portola.

30 Clinical

Pharmacy Practice News • May 2015

Critical Care

FEEDING GAP continued from page 25

Dr. Rollins underscored the shortcomings of retrospective data, which currently predominate malnutrition research. Given the limits of such data, “we’re still in a quandary,” she said. “But the more data we can put into the equations, hopefully the closer we are.” Clinical judgment will always be required, she added, as no one equation will ever spit out the perfect answer for every patient’s nutritional needs.

Challenging Measures The failure to recognize malnutrition in critically ill children often results from not recording weights and lengths. Dr. Mehta noted that these measurements are not just relevant for detecting the nutritional status of patients, but are also “crucial for all aspects of care”— from ventilator and fluid management to medication dosage. In another study presented at the A.S.P.E.N. meeting (abstract 29), Vijay Srinivasan, MD, and his colleagues evaluated anthropometry measurements

following admission to the Children’s Hospital of Philadelphia’s PICU. The hospital requires measurements be made within 24 hours of admission, said Dr. Srinivasan, an assistant professor of anesthesiology for critical care and pediatrics at Perelman School of Medicine at the University of Pennsylvania. Yet staff compliance fell “dismally” short of that standard when they conducted a baseline audit in 2011 and 2012. To improve that performance outcome, Dr. Srinivasan worked with an interdisciplinary quality improvement

team of ICU parenteral nutrition clinicians. In addition to educating staff about the importance of taking measurements, they offered computer-based and hands-on training on the use of equipment. That equipment now includes new length boards and PICU beds that can take weights. The team also modified the electronic health records (EHRs) with prechecked orders to obtain anthropometry following PICU admission. After allowing time for the staff to adjust to the protocol, they re-evaluated compliance—prospectively collecting anthropometry data from the EHRs of all patients for 12 weeks in 2013. Most anthropometry orders did improve compared with the baseline audit: weight (56% vs. 85%; P<0.001), stature (5% vs. 81%; P<0.001) and head circumference (8% vs. 37%; P<0.001). Compliance with orders for recurring weight measurements also increased (23% vs. 40%; P<0.001). Still, the PICU fell short of acceptable standards. Dr. Srinivasan said that they are redoubling efforts to improve anthropometry performance after PICU admission.

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Several other efforts are also underway at his hospital. To support fatigued and overburdened nurses, Dr. Srinivasan and his colleagues recently began exploring how nursing aides may help obtain measurements. His team just completed an international survey of the potential barriers to anthropometry and identified differences in perceptions of these barriers between ordering providers and nurses ((Am J Crit Care, in press). Based on these findings, they are now pursuing targeted education for various clinician groups. Even when anthropometry measures are attempted, other factors can get in the way. Dr. Srinivasan noted the difficulty, for example, in obtaining length measurements of sick kids, especially those with cerebral palsy. So, his team is also looking to identify potential surrogate measures, such as mid-arm span or knee-to-heel length. Given common fluid shifts in the ICU, Ms. Ludwig added the possibility of using triceps skinfold and mid-upper arm circumferences in conjunction with weight. Meanwhile, Dr. Mehta’s institution is now raising awareness for this critical component of care with a program they call “Weights on Wednesdays”—an initiative by the critical care nurses to facilitate weight and height measurements at least once a week. “Something simple like that can go a long way,” he said. —Lynne Peeples Drs. Mehta, Srinivasan, Ludwig and Rollins reported no relevant ﬁnancial conﬂicts of interest.

Clinical 31

Pharmacy Practice News • May 2015

Oncology

New Option for Neutropenia Prevention N

eutropenia and infectious complications after chemotherapy result in an estimated 200,000 to 330,000 hospitalizations among all U.S. cancer patients, so prevention could reduce considerable morbidity among these fragile patients. Treatment is available for this common side effect of myelosuppressive chemotherapy, but patients must return to their health care providers (HCPs) at least 24 hours after chemo to receive it, which they do not always do, according to Amgen, which distributes pegfilgrastim (Neulasta), a leukocyte growth factor, indicated for the prevention of neutropenia after cytotoxic chemotherapy. To increase adherence, Amgen developed the Neulasta Delivery Kit, which includes a single-use prefilled syringe co-packaged with an On-body Injector (OBI, picture below) for Neulasta. The kit will enable the HCP to initiate administration of Neulasta on the same day as chemotherapy with delivery of the full dose the next day.

In some areas and for some patients, such as seniors, returning the next day can be a hardship, explained Ashwin Kashyap, MD, FACP, a medical oncology/hematologist at Tri-Valley Oncology Hematology, in Thousand Oaks, Calif. Even patients who are motivated to return for their shot might appreciate the new product’s convenience, he added. A Phase I pharmacokinetic study demonstrated that the OBI offers comparable pharmacokinetics to Neulasta delivered by the prefilled syringe for manual use, the company said. The kit includes patient instructions and reference quide. On the same day as a chemotherapy session, the HCP initiates Neulasta administration by using a copackaged syringe to fill the injector and activate it. The OBJ is applied to the patient, and Neulasta is delivered about 27 hours after the administration of chemotherapy. Activation of the injector leads to the subsequent insertion of the subcutaneous cannula while under HCP supervision. Dr. Kashyap, whose center has used the device, said it was easy for staff to administer. Patient acceptance has been

mixed, he added. “Some patients like it because of the convenience, but I had one patient who said it was uncomfortable,” and she had trouble sleeping with the OBJ, but added that choosing a different site might address her concerns. In a pivotal clinical trial, in patients with nonmyeloid malignancies undergoing myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia,

treatment with Neulasta significantly reduced the incidence of febrile neutropenia as well as hospitalizations related to febrile neutropenia and the use of IV antibiotics (Cancerr 2006;106:2258-2266). “Neulasta OBI gave us the opportunity to administer a necessary medication without patients returning to the clinic,” said Julie Watson, PharmD, pharmacist in charge, Southeast Nebraska Cancer Center, in Lincoln. “Every little thing

we can do to help our patients have a better experience through their journey, improves their quality of life. Priceless.” Devices such as this one are used in other diseases, “so it is not recordbreaking, but it is new in oncology,” Dr. Kashyap said. —Marie Rosenthal Drs. Kashyap and Watson reported no relevant ﬁnancial conﬂicts of interest.

IMPORTANT CORRECTION OF DRUG INFORMATION ABOUT EXPAREL® (BUPIVACAINE LIPOSOME INJECTABLE SUSPENSION) Pacira Pharmaceuticals, Inc., received a warning letter from the US Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP) on September 22, 2014 concerning an advertisement for EXPAREL, which you may have seen published in several professional journals. This publication provides important corrective information about the false and misleading claim. The FDA stated that the advertisement was false or misleading because it overstates the efficacy of EXPAREL. The FDA objected to the claims that EXPAREL provides pain control that lasts for up to 72 hours because the claims suggest that EXPAREL has been shown to provide pain control beyond 24 hours. According to the Prescribing Information, “The primary outcome measure was the AUC [area under the curve] of the NRS [numeric rating scale] pain score (cumulative pain scores) collected over the first 72 hour period.…In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity.” Excerpts from the applicable sections of the FDAapproved package insert for EXPAREL follow. The FDA has reviewed and approved this communication. Indication for EXPAREL EXPAREL is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated for administration into the surgical site to produce postsurgical analgesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Clinical Studies Hemorrhoidectomy The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72 hour period. There was a significant treatment effect for EXPAREL compared to placebo. ©2015 Pacira Pharmaceuticals, Inc. Parsippany, NJ 07054 PP-EX-US-0623

2/15

In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity; however, there was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated. Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL. Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL as with other local anesthetic products. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. In clinical trials, the most common adverse reactions (incidence ≥10%) following EXPAREL administration were nausea, constipation, and vomiting. Reporting Adverse Events Heath care providers and patients are encouraged to report adverse events in patients taking EXPAREL to Pacira at 1-855-793-9727. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see accompanying brief summary of Prescribing Information.

32 Clinical

Pharmacy Practice News • May 2015

Oncology

Few Approved Targeted Therapies for GE Cancers Austin, Texas—In the United States alone, gastroesophageal (GE) cancers cause more than 15,000 deaths each year. Although much is known about the various pathways involved in the development and progression of GE cancer, finding effective targeted therapies for this disease remains somewhat elusive. Two targeted agents are approved for GE cancer, and many are being studied, explained Shrina Duggal, PharmD,

BCOP, who reviewed some of this research at the annual meeting of the Hematology/Oncology Pharmacists Association held recently. “We still have a lot to learn about the molecular components of GE cancers,” said Dr. Duggal, who is a clinical pharmacy specialist at the University of Pittsburgh Medical Center Cancer Center in Pennsylvania. Surgery with or without radiation or chemotherapy is the standard of care

for patients with GE cancers. However, there are patients with unresectable tumors, and who develop metastatic or advanced disease regardless of therapy. Targeted therapies are being investigated in the adjuvant setting after resection, according to Khaldoun Almhanna, MD, MPH, a medical oncologist of the Department of Gastrointestinal Oncology at H. Lee Moffitt Cancer Center and assistant professor of oncology at the

EXP-AP-0020-201301

University of South Florida College of Medicine, both in Tampa. The primary signaling pathways to target are the human epidermal growth factor receptors, HER2 and EGFR; vascular endothelial growth factor (VEGF); the ligand, hepatocyte growth factor (HGF); the receptor tyrosine kinase MET; the lipid kinase, phosphatidylinositol 3-kinase; the family of serine threonine kinases Akt; and the mammalian target of rapamycin (PI3K/Akt/mTOR). HER2 is overexpressed in about 35% of GE cancer patients ((Lancett 2010: 376[9742]:687-697), but the prognostic implications of this are unclear, Dr. Duggal said. Some studies have associated HER2 with aggressive disease and poor prognosis. Because of the experience with breast cancer, she said, “HER2 is a great target in terms of knowing how to manage these patients. If patients do have HER2-positive disease, it certainly gives us the option of trastuzumab [Herceptin, Genentech], and potentially pertuzumab [Perjeta, Genentech] and T-DM1 [adotrastuzumab emtansine].” Based on the ToGA (Trastuzumab for Gastric Cancer) trial of 584 HER2-positive patients with advanced gastric or gastroesophageal junction (GEJ) cancer that compared trastuzumab plus chemotherapy with chemotherapy alone, trastuzumab was approved to treat patients with advanced GE and gastric cancers who express HER2. Additive antitumor effects have been seen when trastuzumab was combined with capecitabine or fluorouracil (FU) plus cisplatin, she said. ToGA researchers saw significant improvement in all of the end points. The median overall survival (OS) improved from 11.1 months with chemotherapy alone to 13.8 months with chemotherapy plus trastuzumab ((P=0.0046). The duration of response was also significantly improved from 4.8 to 6.9 months. And the overall response rate (ORR) was 35% in the chemotherapy group and 47% in the trastuzumab group ((P=0.00175). The side-effect profile was similar in both groups ((Lancett 2010;376:687-697). JACOB is a Phase III study using a combination of pertuzumab, trastuzumab and chemotherapy in patients with HER2-postitive metastatic gastric or GEJ cancer. In breast cancer, using pertuzumab plus trastuzumab blocks the HER2 receptor. The aim of the ongoing JACOB trial is to determine whether the results will carry over to GE cancers. VEGF-A is a key mediator of physiologic and pathologic angiogenesis. Its activity is mediated by two tyrosine kinase receptors (VEGFR-1 and VEGFR-2). Several anti-VEGF drugs have been used in gastric cancer. Dr. Duggal

Clinical 33

Pharmacy Practice News • May 2015

Oncology

trastuzumab in first-line therapy, and ramucirumab for second-line or beyond. The National Comprehensive Cancer Network recommends a two-drug chemotherapy combination except for those patients who can tolerate more aggressive therapy. There are occasions where a three-drug regimen would be appropriate, Dr. Duggal said. —Marie Rosenthal Drs. Duggal and Almhanna reported no relevant ﬁnancial conﬂicts of interest.

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RAINBOW also investigated ramucirumab in combination with paclitaxel versus paclitaxel alone in patients with advanced or metastatic GE cancer who failed first-line treatment or progressed on a 5-FU– or cisplatin-based regimen. The median PFS was 4.4 months in the ramucirumab combination arm versus 2.9 months in the placebo arm ((P<0.0001). Median OS was 9.6 versus 7.4 ((P=0.017) and ORR was 28% over 16% ((P=0.0001) ((Lancet Oncoll 2014;15:1224-1235). “There is certainly an improved benefit with ramucirumab over paclitaxel, so this is now regarded as our standard of care for patients with advanced gastric cancer who progressed on cisplatinbased therapy,” Dr. Duggal said. Regorafenib is being looked at in the INTEGRATE trial, a Phase II trial for GE patients with unresectable disease unresponsive to chemotherapy. Early results showed that PFS had improved significantly over placebo (11.1 vs. 3.9 weeks in the placebo arm) ((J Clin Oncoll 2014 Mar;3(1):6 2013 suppl; abstr TPS4157). “This drug has major promise and we are hoping to see overall survival rates by the end of the year,” she noted. Onartuzumab (MetMab, Roche), a humanized monovalent monoclonal

—Shrina Duggal, PharmD, BCOP

or GEJ. Results are expected later this year, according to Dr. Duggal. Overexpression of EGFR has been seen in up to 55% of tumors and like HER2, EGFR is associated with aggressive disease and poor prognosis. Several Phase III trials (EXPAND and REAL3) have evaluated targeted therapies against this pathway, but to date, the results have not been promising, Dr. Duggal said. Until more is known about targeted therapies for GE cancers, only two targeted therapies have been approved:

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“We still have a lot to learn about the molecular components of GE cancers.”

antibody directed against the hepatocyte growth factor receptor (c-Met), has potential antineoplastic activity. Onartuzumab binds to the extracellular domain of c-Met, preventing the binding of its ligand, HGF. c-Met, a receptor tyrosine kinase, is overexpressed on the cell surfaces of a variety of cancer cell types and may play a role in their proliferation, spread and survival. Onartuzumab is being studied in the MetGastric trial of 800 patients with metastatic HER2-negative and METpositive adenocarcinoma of the stomach

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discussed bevacizumab [Avastin, Genentech], ramucirumab [Cyramza, Lilly] and regorafenib [Stivarga, Bayer]. Using any of these agents should block VEGFR and inhibit blood vessel formation. The AVAGAST (Avastin in Gastric Cancer) Phase III trial randomized 774 patients into two arms: standard twodrug treatment and standard treatment with bevacizumab. The study did not meet the end point of improving OS ( =0.1002), only improving survival by (P a little more than one month (6.7 vs. 5.3). However, there was improvement in progression free survival (PFS) and ORR ( =0.0037 and P=0.0315, respectively) ((J (P Clin Oncoll 2011;29:3968-3976). “But without having significant survival improvement, it is difficult to make a case to use this drug consistently in patients,” Dr. Duggal said. The Phase III REGARD trial examined another VEGF inhibitor, ramucirumab, with placebo and best supportive care in 355 patients with GEJ disease. There was an improvement in all primary end points. Including median PFS (2.1 vs. 1.3 months; P<0.0001) and median OS (5.2 vs 3.8 months; P=0.047) ((Lancet 2014;383:31-39).

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34 Operations & Management

Pharmacy Practice News • May 2015

Quality Improvement The patient as consumer:

Hospitals That Score Big on HCAHPS Survey P

harmacy leaders at Community Hospital in Munster, Ind., decided to start small, targeting the orthopedics unit only, when they looked at whether a pharmacy education and dispensing program could boost the 435-bed facility’s patient satisfaction scores. Their goal: to encourage more patients to fill their medications through the hospital’s outpatient pharmacy, while providing some related education. The two-month pilot program paid off, both in better scores on the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey and increased pharmacy revenue, according to the hospital’s analysis of the program. Specifically, the facility’s HCAHPS score for communication about medications increased to an average of 73.1% compared with 68.5% before the program’s start. Nearly one-third of orthopedic patients—30.6%—who went home from the hospital filled their medica-

The hospital added a full-time pharmacist and technician to support it, said Beth Clements, PharmD, the hospital’s pharmacy director, who anticipates that the initiative holds long-term promise. There was “an increase in the volume of prescriptions being filled in our retail pharmacy, and increased revenue from such,” she said. “Then overall if we have fewer [hospital] readmissions and an increase in HCAHPS scores overall, it will help with our value-based purchasing.” For many years, hospital pharmacists have been advocating that their clinical skills should be used more on the floors, rather than just behind the pharmacy counter. Since its rollout in 2008, the HCAHPS survey has added weight to that argument. Along with being publicly reported, the scores elicited by the 32-item questionnaire are starting to be tied to reimbursement, in part due to the Affordable Care Act.

‘We felt that every patient should know who their pharmacist or pharmacist extender is.’ —Osmel “Ozzie” Delgado, MBA, PharmD, FASHP tions through the pharmacy. As a result, net revenue associated with the pilot study was more than $1,500, according to the findings. (The researchers noted that the figure was low because it only included orthopedic patients and also only covered the two months of the pilot study, versus a full-year extrapolation.) Community Hospital started to expand the medication discharge service to all inpatient units in fall 2014.

These pharmacy-driven initiatives are laudable in their efforts to make care more patient-centered, said Frank Federico, RPh, the executive director at the Institute for Healthcare Improvement (IHI) in Cambridge, Mass. But the development of these efforts does face several challenges, among them the necessary time and resources to rework schedules or add related positions, he said. Pharmacy leaders interviewed

acknowledge that it can be difficult to maintain forward momentum after the initial rush of effort. At Community Hospital, the percentage of discharge medications filled through the program dropped significantly once the orthopedic effort expanded to all hospital units. But it’s important not to give up, as better medication education can assist patients in the here and now, as well as hopefully improve quality-related measures in the years ahead, said Osmel “Ozzie” Delgado, MBA, PharmD, FASHP, lead researcher on a study published in 2014, which showed that engaging pharmacy students in certain aspects of patient care significantly improve some HCAHPS scores. “We felt that every patient should know who their pharmacist or pharmacist extender is,” said Dr. Delgado, who is the chief operating officer at Cleveland Clinic Florida in Weston. “For us, the most important thing is to get in front of patients, and get that interaction going.” In 2011, Cleveland Clinic Florida started to ramp up medication education

opportunities for pharmacy students, who they viewed as an untapped resource. “Students possess valuable knowledge that that we can leverage,” said Dr. Delgado, who was serving in another administrative role at that time that included pharmacy oversight. Plus, students are blessed with scarce capital—a bit more time to sort through and ferry patient questions, Dr. Delgado said. “Sometimes patients don’t want to feel rushed,” he said. “They get a flurry of information thrown at them, and they probably retain only so much of it.” To that end, the 155-bed teaching hospital expanded its affiliations with nearby pharmacy schools. By 2013, 226 pharmacy students—primarily fourthyear and some third-year—were rotating through annually compared with 98 students in 2011. A student is assigned to each patient, ideally to follow them throughout the hospital stay, stopping by daily to review medications and answer any questions, Dr. Delgado said. The attending pharmacist serves as backup if the student encounters a question or see HCAHPS SCORES, page 36

Coming in June An oncology pharmacy service wins its hospital an ASHP “Best Practices” Award for implementing an EHR system that yielded major reductions in chemotherapy errors.

A new pharmacogenomics clinic—one of the few to be fully integrated within a healthsystem—has proven to be a life-saver for patients with genetic defects that affect drug metabolism.

What anesthesiology and pharmacy departments can do to ease the effects of chronic drug shortages in the operating room.

How to tackle the damaging affects of polypharmacy in end-stage renal disease.

Management tips for pulmonary hypertension, from a hospital that has gained expertise in treating the rare disorder.

A new warfarin reversal protocol from the anticoagulation experts at clotcare.com is being lauded for its efficacy in managing uncontrolled bleeds.

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36 Operations & Management

Pharmacy Practice News • May 2015

Quality Improvement

HCAHPS SCORES continued from page 34

issue that he or she is unsure how to handle, he said. The patients noticed the heightened attention. The percentage who responded “always” on the “communication about medicine” domain score on the HCAHPS survey increased from 58% in January 2012 to 70% 18 months later, according to findings published in the American Journal of Health-System Pharmacyy (2014;71:1871-1876). Cleveland

Clinic Florida also identified a notable bump in the percentage of patients being discharged with medications filled through the pharmacy—up from 48% to 65% during the 2012 calendar year.

students and a medical-surgical unit, the students would visit patients shortly after their admission, ideally within 24 hours, according to Edna Cheung, PharmD, BCPS, the pilot study’s project leader and a staff pharmacist at Magee-Womens. The student would introduce himself or herself, explain the pharmacy’s role and alert the patient that a pharmacist would return to answer any medication questions before discharge. The interns were provided a bit of a script that included words like “new medicine”

Students Become the Teachers At Pittsburgh’s Magee-Womens Hospital of UPMC, pharmacy leaders similarly decided to incorporate the skills of pharmacy students, albeit on a smaller scale, to forge better connections with patients. During the 2013 pilot program, which involved four pharmacy

KCENTRA® (Prothrombin Complex Concentrate [Human]) For Intravenous Use, Lyophilized Powder for Reconstitution Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kcentra safely and effectively. See full prescribing information for Kcentra. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential beneﬁts of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding. • Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. • Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. ---------------------------------INDICATIONS AND USAGE-----------------------------------Kcentra, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deﬁciency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with: • acute major bleeding or • need for an urgent surgery/invasive procedure. -----------------------------DOSAGE AND ADMINISTRATION--------------------------------For intravenous use only • Kcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight. • Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished. • The safety and effectiveness of repeat dosing have not been established and it is not recommended. • Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min.).

Pre-treatment INR

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and “side effects,” which appear in some of the medication-related HCAHPS questions, Dr. Cheung noted. Before discharge, the pharmacist would stop by and along with answering questions, would provide a small medication card (see below) that detailed a short list of side effects and several other key details for each new medication the patient was taking. (The back of the card includes a disclaimer, with language stipulating that “this medical information is not intended to be used as a substitute for professional medical advice, diagnosis or treatment.”) The pharmacy, which is still building a database of such cards, had created roughly 90 for various medications by early spring. Magee-Womens’ overall medication communication score for the medicalsurgical unit, which had been hovering just slightly above 50% in the two years before the discharge education initiative, increased to 65% during the six months of the project, according to Dr. Cheung.

* Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20-31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡ Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

--------------------------------DOSAGE FORMS AND STRENGTHS-------------------------• Kcentra is available as a single-use vial containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S as a lyophilized concentrate. -------------------------------------CONTRAINDICATIONS ------------------------------------Kcentra is contraindicated in patients with: • Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin. • Disseminated intravascular coagulation. • Known heparin-induced thrombocytopenia. Kcentra contains heparin. --------------------------------WARNINGS AND PRECAUTIONS-----------------------------• Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment. • Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. • Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ------------------------------------ADVERSE REACTIONS--------------------------------------• The most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. • The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis. To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-9156958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------USE IN SPECIFIC POPULATIONS---------------------------------Pregnancy: No human or animal data. Use only if clearly needed. Based on March 2014R version.

At Pittsburgh’s Magee-Womens Hospital, prior to discharge, pharmacists give patients a small medication card that includes a short list of side effects and several other key details for each new medication the patient is prescribed.

But not all HCAHPS-targeted projects tackle the full spectrum of medication education. At Capital Health Regional Medical Center in Trenton, N.J., the decision was made to focus limited resources on one complex drug, specifically warfarin, to see if the educational intervention could be maintained and would achieve a HCAHPS impact, said Daniel Abazia, PharmD, BCPS, a clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers University, Piscataway Township, N.J. “Warfarin is the type of drug that most adults have at least heard of at some point either themselves or from family or friends, and often bad things about it,” said Dr. Abazia, who coordinated the warfarin project at Capital Health, his practice site. “So we spend more time on the medication. And oftentimes, we end up talking about other meds because there are so many interactions.” During the pilot, which extended from June to December 2013, 108 patients

Operations & Management 37

Pharmacy Practice News • May 2015

Quality Improvement were educated, all of whom had just started the blood thinner. The facility’s medication HCAHPS score increased to 63.2% for the seven months of the project compared with 57.6% for the prior calendar year. Although the warfarin education continued after the pilot, the facility has not sustained that higher score. In 2014, the medication communication average was 59.4%, according to data provided by Dr. Abazia. Why did the HCAHPS score decline? One possible factor is that more patients are being prescribed one of the newer anticoagulants, decreasing the number that can be reached by focusing on warfarin, Dr. Abazia said. The monthly average of patients seen by the warfarin project decreased in 2014 compared with the pilot period. To address this issue, Dr. Abazia is working on a way to better flag patients started on any type of anticoagulant, so they can be reached before leaving the hospital. “My hypothesis is that the more people you see, and you provide good patient education, the [HCAHPS] scores will get better,” he said. Sustaining a promising start also proved to be a challenge at Indiana’s Community Hospital once the pilot ended. Although 30.6% of patients during the pilot discharged home had their prescriptions filled by the hospital pharmacy, that capture rate dropped to 5.28% for the first three months after the service was expanded to all inpatient hospital units. In some respects, focusing on the orthopedic service was easier, as it was a limited service area and those patients tend to be discharged during the outpatient pharmacy’s hours of operation, according to pharmacy leaders at Community Hospital. But although the capture rate did decline once the dispensing service went hospital-wide, the total number of medications filled is much higher, they said. Along with striving to increase that medication capture rate, pharmacy leaders are counting their repeat customers. Patients are told they can refill the prescription at their local pharmacy after they go home, but some opt to continue with the hospital’s pharmacy. “From a loyalty standpoint, the business in the outpatient pharmacy has increased because of repeat customers,” said Sean Chantarapanont, PharmD, a clinical pharmacy manager at Community Hospital. Moving forward, Dr. Delgado foresees ways that boosted interaction with pharmacists and students can improve other HCAHPS scores. For example, pharmacy students checking on patients more routinely can highlight unrelieved pain, another element tracked by several questions on the HCAHPS survey. “Obviously if you are having interactions with the

patient on a daily basis on their medication regimen, and their current medication regimen is not taking care of the pain, that’s going to come up in the conversation,” Dr. Delgado said. To boost pharmacy’s clinical role at the bedside for such initiatives, hospitals don’t necessarily have to add staff, said Mr. Federico, of IHI. In some cases, restructuring the pharmacy service and using all clinicians—from students through clinical pharmacists—to their maximum abilities can make a significant difference, he said.

Close attention also must be paid to how pharmacists communicate with patients, Mr. Federico said. “We have to be able to make sure we’re explaining how to take the medications, the side effects, etc., at a literacy level that all patients will understand.” Mr. Federico encouraged hospital programs not just to focus on high-alert medications such as insulin or warfarin, but watch for another common risky scenario—simply taking too many medications. Given all of the specialists involved with a patient’s care, the

number of medications prescribed can proliferate during the hospital stay, and with that, the potential interactions and side effects, Dr. Federico said. “What if,” he asked, “we work very diligently in minimizing the number of medications that a patient is taking to the essential few?” —Charlotte Huff The sources disclosed no relevant ﬁnancial conﬂicts of interest. Their research was presented at the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists.

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38 Operations & Management

Pharmacy Practice News • May 2015

Practice Models Five Questions for Kyle Skiermont, PharmD

Getting Started in Specialty Pharmacy Fairview Health Services, a University of Minnesota partner health system encompassing seven hospitals and medical centers, launched its own specialty pharmacy in the late 1990s—long before the idea was on the radar for most hospitals and health systems. Today, it’s one of the largest health system–owned specialty pharmacies in the United States. In an interview with Pharmacy Practice News, Fairview Pharmacy Services’ Vice President of Operations Kyle Skiermont, PharmD, shared his insights into the steps needed to successfully launch a hospital-based specialty pharmacy service. at’s the first thing a hospital system debating adding pharmacy should consider? ermont: One of the first key determine the reason why you sted in adding specialty pharmacy. Is it patient care–driven—do you want to make sure you can provide all aspects of care for your patients? Is it a revenue and profit opportunity? Or is it a little bit of both? Most systems will say, “Of course it’s both,” but it’s important to get at the driving force. If your motivation is more financially driven, then dollars and cents are key. Look at how many specialty scripts are being written out of the system. How many do you think you can capture? Can you get the payors in your market? Can you get access to limited distribution drugs? If you’re looking at specialty pharmacy mostly from a perspective of caring for all your patients’ needs, then you may start building things even before you know whether or not you can get in with Blue Cross and Blue Shield in your state.

1 2

at are some of the biggest hospitals and health make when getting into pharmacy? ermont: The biggest mistake is not having a true understanding of what the market expects from a specialty pharmacy—what health plans, pharmaceutical companies and providers expect. Specialty pharmacy is much broader than just “We have Enbrel on the shelf and we can dispense it.” The data-reporting capabilities, the ongoing follow-up and clinical management—health systems are so good at clinically taking care of a patient, but they are often unaware of the market expectations surrounding specialty pharmacy. You can start by looking at the URAC accreditation standards. If you can meet those standards, you’ve got 90% to 95% of what’s expected. Don’t jump in too fast. If you’re going to plans and providers as a specialty pharmacy, you have to do it right the first time because it’s hard to have to go back a second time and say, “Yeah, now we’re really ready.”

pharmacy. But if you want your pharmacy to look like Accredo or Walgreens in order to compete financially, you may build it more or less completely, and then roll it out. Of course, you can do small- or fullbore for either reason, but if you are looking at a huge financial opportunity, that drives a full business plan and going to the health system for millions of dollars of capital. From my experience, patient care–oriented specialty pharmacies start a little smaller—with something like “Our hepatitis docs asked us to try this and then we expanded.”

hat are the main options pital starting a specialty cy? ermont: You have two primary : Do it entirely yourself, or do it with a partner. Once you know the size of the opportunity—the number of scripts and the dollars—that can lead you to a decision about whether you want to go it alone or find a partner, or not do it at all! There are still a few primary care–driven community hospitals that pretty much do the basics, and don’t have a lot of “–ologists” on their staff. If that’s you—if you’re mostly pediatrics, internists and primary care—building a specialty pharmacy may not make sense, even if “everybody else is doing it.” Partnering has many varieties. Maybe you do the dispensing, but you contract out the call center or the shipping.

w does this underlying on drive the type of a hospital or health system uild? ermont: Institutions that are getting into specialty pharmacy primarily from the care perspective might start small, or with a particular clinic, or might have more onsite resources or do specialty out of the retail or discharge

You might partner with someone to do your refill reminder calls, your patient education and the majority of your ongoing interface. Or it might be less robust: You encourage patients to use a particular specialty pharmacy, and that specialty pharmacy feeds clinical data back to you.

w long does all this take? ermont: A very quick launch six months, but more likely it 2 to 24 months. If you’re going the shorter end of the time frame, your health system really has to have bought in and given you the capital you need to get data-mining equipment and software and hire the necessary FTEs [full-time equivalents]. That’s pretty rare. The Cleveland Clinic took years to get approval for its specialty

Video Exclusive

The UIC Approach To Specialty Pharmacy Pharmacy Practice News recently sat down with JoAnn Stubbings, PharmD, the assistant director of specialty pharmacy (SP) at the University of Illinois, Chicago (UIC), to discuss her facility’s approach to breaking into this competitive trade channel. Closed out of most limited distribution networks and excluded by many payors from key SP contracts, Dr. Stubbings and her colleagues nevertheless have been able to add millions of dollars in new revenue by expanding UIC’s SP offerings. For more details, scan the adjacent 2D barcode or visit pharmacypracticenews. com and click in the multimedia pulldown menu at the top of the home page.

pharmacy, but when they got it, they had a 20,000-square-foot facility and the authority to hire 66 FTEs. Banner Health in Phoenix took a similar all-in approach and moved quickly to build its space and hire staff. For many other systems, the right approach is to go clinic by clinic: Start with one, hire a specialty pharmacist, prove that out and then expand to another clinic. —Reported by Gina Shaw

Avella and Sentry Partner To Help Hospitals on 340B

vella Specialty Pharmacy has announced a partnership with Sentry Data Systems to help hospitals and health systems manage their participation in the federal 340B drug discount program. Sentry serves as a third-party administrator for many entities covered under 340B; with a proprietary technology platform, it helps the hospitals and health systems navigate the program’s often thorny compliance, audit

and inventory requirements. Under the new partnership, Avella will provide all the fulfillment of specialty medications for Sentry’s clients. “They do all of the validation and administrative support, while we will provide all the clinical support of the patient and the drug fulfillment,” Nancy McCutcheon, Avella’s senior vice president for strategic sales, told Pharmacy Practice News. “We have access to many limited-distribution drugs

that many other pharmacies, especially specialty pharmacies, do not, as well as a track record of excellence in patient care.” Given the complex requirements of the 340B program—and the growing number of audits being conducted— the need for compliance help is clear. The Health Resources and Services Administration (HRSA), which administers the 340B program, has stepped up its oversight.

As of late 2014, nearly 250 audits had been performed, according to an HRSA spokesperson. More are expected in 2015. Any covered entity that fails to comply with 340B program rules may be required to refund the discounted monies to the manufacturers or be removed from the program, and they will be subject to a second audit the following year, according to the agency. —Gina Shaw

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40 Operations & Management

Pharmacy Practice News • May 2015

Leadership in Action

The EQ of Great Leaders Emotional Intelligence: ‘The hidden driver of excellence’

n pharmacy, we are surrounded by colleagues possessing a high IQ. That’s not surprising, given the rigors of our education. We graduate with a doctor of pharmacy degree, often complete one or two years of postgraduate residencies and then sometimes go on to obtain a master’s degree in an MBA or MPH program. After all this education and training, we see two types of leaders emerge: those who are stars—and others who are not. So what accounts for this divergence in people who may have identical scholastic aptitudes, education and training? I submit to you that it is what some people call the “soft skills” of emotional intelligence (EQ) that can make the difference. We conclude our series with this article based on Daniel Goleman’s “Focus, The Hidden Driver of Excellence” (HarperCollins 2013). Goleman is the present-day expert on EQ, having written numerous books and Harvard Business Review articles on the topic. Goleman cites some of the early work done by David McClelland, the founder of McBer, which later became the Hay Group. McClelland argued early on that competencies such as self-discipline, empathy and persuasion were far stronger than academic ranking when it comes to shaping successful people.

Emotional Competence Years ago, I had the good fortune of hiring a consultant who was authenticated to administer the Emotional Competence Inventory (ECI) developed by the Hay Group. This structured assessment included four key quadrants: 1. Self awareness 2. Self management 3. Social awareness 4. Relationship management Within those four quadrants are 20 competencies (see chart). The administration of the tool included a self-evaluation, as well as evaluations by my manager, peers, direct reports, client/customers and others, for a total of 19 evaluations. The results of the assessment were very enlightening and identified my strengths and weaknesses from an EQ perspective. Most leaders have typically completed an assessment of managerial styles, such as a Myers-Briggs or a myriad of other similar tools; however, not many have completed an ECI. According to Goleman, research by the Hay Group has shown that leaders who show strengths in eight or more categories had created highly energizing, top-performing work climates; those with three or fewer strengths in

people skills created negative climates. The ECI shows that self-awareness and self-management allow the leader to have social awareness and develop positive relationships with others.

Systems Awareness Systems awareness is the understanding of the “big picture,” which allows one to visualize the dynamics of decision making not only in complex systems and determine the effect of those decisions at a distant point, but also at the local level (e.g., the pharmacy department). This vision is sorely needed in today’s rapidly evolving health care landscape. The current movement toward population health, for example, is fundamentally changing the way we practice. Do you have the vision to see how that trend might affect pharmacy operations? Can you devise a strategy for getting your pharmacy in alignment with your vision? Can you communicate that strategy and implementation plan with passion and skill, drawing on the cognitive and emotional empathy of your co-workers and subordinates to pull off the plan? Finally, have you set up a review process to analyze the results and tweak the process, starting from the top again? Daniel Friedland, MD, the founder and CEO of SuperSmartHealth, calls this process the VSIR cycle—Vision, Strategy, Implementation and Results—in his “4 in 4 Framework to Achieve Peak Performance,” an online productivity program (http://goo.gl/tOX3KQ). Q Thinking in terms of systems allows you to develop a vision; however, the skills to design and implement that vision require EQ. This is a team process, but it starts with the individual leader and should draw on every skill that leader possesses. These leadership strategies have moved health-system pharmacy from a practice that is focused primarily on the traditional inpatient arena to one that also embraces outpatient areas of care, including clinics, physician practices and patient homes. Pharmacists who are involved in such a model typically provide medication reconciliation, medication therapy management, direct patient care and patient education, and they’re doing so in patients for whom the system assumes some financial risk based on predetermined outcomes. To be successful, this model requires multidisciplinary care that is delivered across multiple sites, and I would submit that it also requires the EQ skills of self-discipline, empathy and persuasion. As Goleman stated,

“The well-focused leader balances the data streams each offers, weaving these strands into seamless action. Putting together data on attention, with that on emotional intelligence and performance, this triple focus emerges as a hidden driver of excellence.”

Know Yourself Who are the most influential leaders in your group? Often they may not be the positional leaders, but will be those individuals who are highly skilled in EQ and have high levels of self-control, empathy, influence and cooperation. Successful leaders take advantage of the informal leaders of a group. Successful leaders mentor and advise their groups. This starts with clearly articulating your vision and expectations, and in the process passionately exciting people about the direction you’ve boldly set. But it’s

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at ernestanderson1130 @gmail.com

Ernest R. Anderson Jr., MS, RPh

In a department, the collective emotions are often identified as its “climate” or “culture.” EQ enables the tuned-in leader to detect this climate and instill change or encouragement as needed. This requires listening, observing, asking probing questions, reflecting the insights and perspectives of others in an active process. Think of this skill as your personal radar as a leader—it needs to be on at all times. Don’t let issues fester; listen for the unspoken issues that you perceive through observation and your gut.

Emotional Intelligence: The Competency Framework Self

not a one-way street: Coaching and listening to people’s personal vision with empathy also shows you care. Developing the consensus of strategy through collaboration instills “buy-in” for each individual. Celebrating the wins for the group builds emotional capital and is highly motivating. Adept leaders can read their employees as a group, while at the same time looking for signs that certain individuals may need further guidance. Subtle cues of facial expression or voice inflect, for example, may show fear, anger or other emotions that signal it’s time to drill in to determine who needs individual attention.

Others

The Final Assessment We are living in an exciting, transformative era for pharmacy. But to truly benefit from these changes requires great leadership and vision. We must be able to think beyond what is right before us and see the goal of the future as well. It is like an expert archer overshooting at the apparent target several yards away and crying “bull’seye” to everyone’s amazement as he hit the far target that no one was even focused on. Go and do likewise. ■ For more information, visit Daniel Goleman’s website at http://goo.gl/p1kBT4.

Operations & Management 41

Pharmacy Practice News • May 2015

Leadership

Pharmacy Directors Take Two Paths to the C-Suite A

fter graduating from the University of Kansas School of Pharmacy in 1988, Michael D. Sanborn, MS, BSPharm, FASHP, was eagerly looking forward to a career as a clinical pharmacist. A little over a decade earlier, at the University of Tennessee College of Pharmacy in Memphis, William E. Evans, PharmD, had his mind set on combining a clinical pharmacy practice with a competitive research program.

abilities, the energy to set new goals and seek out new career opportunities and a belief in the value of patience and teamwork in achieving strategic aims. Most important perhaps was their readiness to take on the rigors of hospital leadership. “You’ve got to want to do this job,” Mr. Sanborn said. The greater responsibilities and longer hours can be stressful, he noted, but also rewarding.

As a hospital leader, ‘you get to open doors not only in the pharmacy but in every department in the organization.’ —Michael hael D. Sanborn, MS, BSPharm, FASHP

Neither harbored though hts about one day leading a largge health care organization. Yet today, Mr. Sanborn is the t president and CEO at Baylor Medical Center in Carrollton, Texas, and Dr. Evans, after a decade as director and CEO at St. Jude Children’s Researcch Hospital in Memphis, presidess over a research laboratory that iss seeking new breakthroughs in childhoo od cancer treatments. Dr. Evans, the author or co-author of more than 150 research papers over the past 15 years, said his “winding road” to the executive suite involved “a lot of on-the-job training and watching really successful people—not any formal management training or MBA.” As a young pharmacist-researcher starting out at St. Jude, he willingly took on increasingly demanding management roles, starting with director of pharmacy and advancing to executive vice president and chief science officer, and finally, in 2004, to CEO. He never gave up his National Institutes of Health research grant (recently renewed through 2020) and has led a research team throughout his career. Mr. Sanborn’s managerial route was more circuitous, with stops at Parkland Hospital in Dallas, the University of Kansas Medical Center in Kansas City, the NCH Healthcare System in North Naples, Fla., and the McKesson Corporation as corporate vice president, before finally landing, in 2003, at Baylor University Medical Center as director of pharmacy. Although their career paths differed, they shared certain qualities and values that prepared them well for the challenges of the C-suite: among them, an innate confidence in their leadership

“As a pharmacy director,” he said, “one of the things I always loved was having the opportunity to open doors to new clinical programs—to put pharmacists in places they had never been, like the emergency room and medication reconciliation and rounding on patient floors.” As a hospital leader, he added, “you get to open doors not only in the pharmacy but in every department in the organization. “Being a pharmacy director,” he said, “prepared me wonderfully for serving as a CEO.” As for autonomy, Dr. Evans called it “a myth” that hospital CEOs don’t have bosses. “You have many bosses,” he said, “They’re your board.” At St. Jude, his boss happened to be 50 people “all quite divergent in their backgrounds,” he said. “Most didn’t have expertise in health care or research,” he added, and it took patience dealing with a group that might not have always asked “the right questions, but who were enormously passionate and wanted to do the right thing. It was my job to translate their passion into progress.” Both Dr. Evans and Mr. Sanborn said that the analytical skills and clinical training they received as pharmacists, along with their career-long interactions with physicians, nurses and other

professional staffs, were important factors in their ability to handle larger C-suite responsibilities. They also agreed that pharmacists and pharmacy directors who are thinking about administrative roles should look within and outside their hospitals for opportunities that expand their horizons beyond pharmacy. Dr. Evans suggested that “the best way to get your foot in the door” is to volunteer for committees or task forces assigned to “accomplishing something at an institutional level.” It might be “implementing new features in an electronic health record system, developing a new clinic or clinical service, or evaluating medication safety,” he said. “There are lots of opportunities for pharmacists to get involved and begin to exert their influence on an organization level.”

Ernest R. Anderson Jr., MS, FASHP, a pharmacy leadership consultant and former system vice president of pharmacy at Seward Health Care, headquartered in Boston, agreed with Mr. Sanborn that “pharmacy directors do make good hospital administrators.” He said that although relatively few pharmacists currently serve as hospital CEOs, “one of the trends I’m seeing—even in some of the smaller hospitals—is for pharmacy directors to be given more and more responsibility for managing other departments.” One reason, he said, is that pharmacy managers have drawn increased attention from administrators because of the growing importance that medications play in keeping people well and reducing cost costly readmissions. Another is their sskill in managing the everlarger slice of hospital budgets that drugss consume. “They respond to thee scrutiny,” he said, and get noticeed as potential candidates for the C-ssuite. Ph harmacy managers are also veery adept, Mr. Anderson said, “aat looking at the big picture in health care” and in putting theirr departments in the context of whaat is going on nationally in Medicare, m managed care, commercial insurance an nd other developments that affect multip ple hospital departments.

‘There are lots of opportunities for pharmacists to get involved and begin to exert their influence on an organization level.’ —William E. Evans, PharmD Mr. Sanborn advised pharmacy directors to volunteer to take over another department on an interim basis whenever the need arises. “I’ve managed lots of departments, including some nursing departments, when I was a pharmacy director,” he said. “I became known as someone they could call on to pinch hit when they were tight on leadership. It really can be a way to have people recognize your leadership skills beyond pharmacy.” But rising to top management as a pharmacist also requires being in the right place, Dr. Evans noted. “Find the right organization that has that openmindedness,” he recommended, “one that is looking for people who have bright ideas and can lead, not necessarily people with a certain set of credentials. I’m just lucky to be at one of those organizations. I think it’s happening more and more these days.”

“Pharmacy has become the focal point for everybody in the hospital,” he added. —Bruce Buckley Based on a joint session at the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists, in Anaheim, Calif., as well as follow-up interviews.

42 Technology

Pharmacy Practice News • May 2015

Patient Safety

SENTINEL EVENT continued from page 1

• A pharmacist had two patient records open, was interrupted and subsequently ordered medication for the wrong patient. These mistakes can happen at any point in the process from ordering to administration, from anyone or anything—including IT systems, according to Lisa Buczkowski, RN, the associate director of the Office of Quality and Patient Safety at the Joint Commission.

“It could be IT [at fault] as part of the team, because of the design of the electronic elements being used,” Ms. Buczkowski said. Indeed, although many technologies, such as clinical decision support systems (CDSS) within an EHR, have been introduced to avert medication errors, they still occur, noted Holly Lilly, PharmD, pharmacist consultant, IT and automation projects at Tallahassee Memorial Healthcare, in Florida. She pointed to one of the examples above as a common occurrence, which can

‘When we fire an alert we want you to pay attention to, we don’t want you to be influenced by the nine others that were meaningless.’ —Christina Michalek, BSc Pharm

happen when providers are allowed to keep multiple sessions open within an application.

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“This functionality can be critical if an emergency arises and one does not want to lose complex work in progress,” Dr. Lilly said. “However, the functionality introduces the heightened risk that an order could be entered for a patient other than the one intended. A pharmacist reviewing and verifying orders may or may not detect this issue from the CPOE [computerized prescriber order entry] system.”

Alert Fatigue Clinical alerts within a CDSS are often the culprit in technological medication errors, experts noted. Alert fatigue—when clinicians start arbitrarily overriding clinical alerts because of an overabundance of them—is something that is not receiving enough attention by health care organizations, said Christina Michalek, BSc Pharm, RPh, FASHP, a medication safety specialist at the Institute for Safe Medication Practices (ISMP), in Horsham, Pa. Karl Gumpper, RPh, BCPS, FASHP, team leader of pharmacy informatics at Boston Children’s Hospital and author of the first Joint Commission alert on health IT in 2008, said that a big problem with alerts is that although sometimes they fit in the workflow, other times they’re unnecessary. He used drug–drug interaction as an example. “There are certain drugs you never want together, but then sometimes you do want to get two together but you’re monitoring them anyway and an alert at the ordering process might not be relevant,” Mr. Gumpper said. This is where the usability of health IT systems and their design can be a problem, Mr. Gumpper noted, adding that the Office for the National Coordinator for Health IT, under the Department of Health and Human Services, is working to improve this problem. At 33%, usability was the most frequently cited reason for health IT–related sentinel events in the Joint Commission’s report. Ms. Michalek said it may be necessary to tailor systems to ensure alerts of value are not being ignored. “Find out what’s being overridden more than 90% of the time. See if there are ones that can be turned off that don’t add any value to patient care,” she said. “When we fire an alert we want you to pay attention to, we don’t want you to be influenced by the nine others that were meaningless.”

Technology 43

Pharmacy Practice News • May 2015

Patient Safety Mr. Gumpper said his organization tries to continuously do exactly what Ms. Michalek recommended, looking at the data and fine-tuning alerts to ensure they are only based on priority. This includes looking in the CPOE and EHR systems as well as other areas within the hospital like smart pumps, he said.

Being Proactive Although many tech-related errors are hard to detect because of poor design, they can still be diminished in a prospective safety culture, said

Erin Lawler, a human factors engineer at the Joint Commission’s Office of Quality and Patient Safety. Pharmacists and their staff can recognize when something looks off and need to be empowered to openly speak out when that happens. “It’s each person’s responsibility to look around their work processes and environment and look for that next opportunity where failure can occur,” Ms. Lawler said. Enacting this culture may mean scanning barcodes in advance of medication

administration or double-checking technologies, such as automated medication dispensing, Ms. Michalek said. The Joint Commission recommended ensuring pharmacy dictionaries are loaded and reviewed regularly. Even when IT applications don’t interface with each other, which experts said could help prevent medication errors, Ms. Buczkowski advised pharmacists to figure out ways to circumvent that situation. “If your system can’t get lab results, get lab results,” she said. As many experts have said, including

the authors of the Sentinel Event Alert, errors will not be avoided through improvements in technology design or through culture alone. It happens by building awareness of safety through education and training while developing better engineering design processes in technology. Health care workers can take a free online course for continuing education credit at http://www.jointcommission. org/safe_health_it.aspx. —Gabriel Perna

FDA APPROVAL

Amgen’s Corlanor (ivabradine) Approved For Heart Failure

he FDA has approved Corlanor (ivabradine) to reduce the risk of hospitalization for worsening congestive heart failure (CHF) in patients with stable, symptomatic chronic CHF. Corlanor is the first new chronic CHF medication to be approved by the FDA in nearly a decade, according to Amgen, which markets the drug. Corlanor is intended for use in HF patients who have left ventricular ejection fraction (LVEF) values of ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and who either are on maximally tolerated doses of betablockers or have a contraindication to beta-blocker use, the company noted in a press release. Results from the Phase 3 SHIFT study showed Corlanor significantly reduced the risk for the primary composite end point of hospitalization or cardiovascular death for worsening CHF, with an 18% relative risk reduction versus placebo. The most common adverse drug reactions in the SHIFT study (≥1% of patients) in patients taking Corlanor vs. placebo were bradycardia (10% vs. 2.2%), hypertension or increased blood pressure (8.9% vs. 7.8%), atrial fibrillation (8.3% vs. 6.6%) and visual brightness (2.8% vs. 0.5%). The recommended starting dose of Corlanor is a 5-mg tablet twice daily with meals. After two weeks of treatment, the dose should be assessed and adjusted depending on heart rate. In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose based on heart rate.

WE TAKE PAIN PERSONALLY REASON #1

THE NEED FOR NON-NARCOTIC PAIN MANAGEMENT THERAPY HAS NEVER BEEN GREATER. Hospitals are looking to reduce adverse events and opioid consumption. 1-3 Patients receiving an opioid prescription within 7 days of surgery were 44% more likely to become long-term opioid users within 1 year when compared with those who received no such prescription.4 ON-Q* is proven to reduce the amount of narcotics patients receive after surgery. 5 For more than 16 years, we have been focused on improving patient outcomes. By continuously working together with clinicians to improve catheter placements and block techniques, the ON-Q* Pain Relief System has been able to reduce the amount of narcotics needed to effectively manage post surgical pain—for each patient and procedure.

FOR MORE INFORMATION CALL (800) 448-3569 OR VISIT HALYARDHEALTH.COM/ON-Q

There are inherent risks in all medical devices. Please refer to the product labeling for Indications, Cautions, Warnings, and Contraindications. Failure to follow the product labeling could directly impact patient safety. Physician is responsible for prescribing and administering medications per instructions provided by the drug manufacturer. manufacturer Refer to www www.halyardhealth.com halyardhealth com for product safety Technical Bulletins Buulletins.

PAIN MANAGEMENT YOU CAN DEPEND ON.

1. The Joint Commission. Sentinel Event Alert. A complimentary publication of The Joint Commission. Issue 49, August 2012. 2. Attarian, David E. What is a preventable adverse event? AAOS Now. 2008, May. 3. unknown. (12, December). Lifespan adopts emergency department guidelines created to curb opioid misuse and abuse. Retrieved from http://www.acphospitalist.org/archives/2014/02/coverstoryy.htm. 4. Alam et al. Long-term analgesic use after low-risk surgery: a retrospective study. Arch Intern Med. 2012 Mar 12;172(5):425-30. doi: 10.1001/aarchinternmed.2011.1827. 5. Data on ﬁle. ON-Q* Pain Relief System. *Registered Trademark or Trademark of Halyard Health, Inc. or its affiliates. © 2015 HYH. All rights reserved. RX Only. MK-00754

44 Technology

Pharmacy Practice News • May 2015

Drug Compliance

CMS Funds Hi-Tech Plan for Compliance in HIV

rug adherence is a challenge in most clinical scenarios. But in the case of HIV, where patients’ regimens can include dozens of drugs, compliance tools are in particular demand. VillageCare, a New York City–based nonprofit organization, may have the answer, based on a grant it just received from the Center for Medicare & Medicaid Innovation (CMMI). The center awarded VillageCare $8.7 million for a

three-year project called Treatment Adherence through the Advanced Use of Technology. The initiative centers on an integrated mobile Web and app portal that offers a personalized medication adherence plan, social support, video sessions and text messaging. Part of the high-tech offerings include

“Rango,” an online platform that combines a variety of technology-enabled features into one service that motivates and educates people to manage their own health, according to its developers. More specifically, Rango is a fully secure and anonymous multifaceted Internet tool that features: • A “fun and engaging” online community that allows patients to share

BD PhaSeal™ Closed System Drug Transfer Device Work safe. Enjoy life.

Protecting Jacob the pharmacist, and Jacob the cyclist. Pharmacists often tell us how satisfying it is to be such an important part of a patient’s treatment. But, you’re also important to many other people in your life—so please take care of your health, too. Studies connect hazardous drug exposure to serious health risks for pharmacists. We’re helping to change that, by protecting thousands of pharmacists every day from the hazardous drugs they handle. We can’t do what you do, but we can help you do it safely.

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their stories—both positive and negative—and receive advice and encouragement from their peers. • Moderated discussion boards on a variety of health and healthy living topics. • Professionally facilitated virtual support groups that are held throughout the week and day to maximize accessibility. • Virtual Q&A with a Health Coach, to ask questions that patients may not want to ask in a group, or even ask their doctor or case manager. • Patient-controlled text reminders for adhering to prescribed treatment regimens, attending medical appointments and picking up refills. • A dynamic article library with easyto-understand explanations about HIV/AIDS, common comorbidities, medications and other information • Matching to a trained peer mentor, who can help an individual through specific concerns. Rango is not just for individuals who are struggling with compliance, according to Jessamine Buck, the program director. “Rango creates a community of individuals facing similar issues,” she said. “It is this online community support, combined with personal reminders and professional advice, that will be the key to the program’s success.”

Some Caveats “Anything and everything that can be done to improve patients’ access to care and their medication adherence is a good thing,” Tony Luna, the executive vice president for business development at Aureus Health Services, told Pharmacy Practice News. “This model seems like it could potentially work for a segment of the population living with HIV/AIDS. But we can’t also lose sight of the fact that there are a lot of people living with HIV who are disenfranchised and may not have the financial abilities to have access to reliable and regular tech devices. Those who are homeless, for example, are at even more risk for nonadherence, and it’s very important that we recognize as service providers that not all people living with HIV/AIDS have that consistent, reliable access to the tech tools that so many people take for granted.” He added, “Technology is just one piece of the overall adherence solution.” Medicare and/or Medicaid beneficiaries who have been prescribed medications for HIV/AIDS are eligible to participate in the VillageCare initiative. Participants can access Rango from any computer or smartphone with a username and password. Most features are also available via a standard cell phone. —Gina Shaw

Technology 45

Pharmacy Practice News • May 2015

All photos by Marie Rosenthal

Profiles in Pharmacy

n a town that prides itself on “keeping it weird,” the pharmacists at St. David’s HealthCare in Austin, Texas, like to play it straight—providing a wide range of specialized pharmacy services that improve patient care. Whether it is visiting the Cathedral of Junk, running in the annual Gorilla Run (in costume) or gathering on the Congress Avenue Bridge to watch the bats, Austin, the capital of Texas, is known for its quirky culture, music and great food; but it is also establishing a name for itself in quality health care. St. David’s HealthCare has won numerous awards, including the Malcolm Baldrige National Quality Award, the nation’s highest presidential honor for performance excellence. One of the largest health systems in central Texas, St. David’s HealthCare comprises 110 sites, including six hospitals, across central Texas. “Although we are the same system, each one of our facilities has its own personality and own pharmacy services,” explained Rusty Pendley, RPh, director of pharmacy at St. David’s North Austin Medical Center. “This hospital has grown, especially among our [specialized] services,” he said. “For example, we’ve expanded our women’s services because last year we performed nearly 6,000 births at St. David’s Women’s Center of Texas. We just added a 26-bed antepartum unit with an intensive care unit [ICU],” he said, enabling both mothers and babies to receive needed services faster with specialists in antepartum and neonatal care. Last year saw the opening of the St.

David’s Children’s Hospital, a separate hospital within St. David’s North Austin Medical Center, with a dedicated pediatric emergency department (ED), medical surgical inpatient unit, intensive care services and pediatric pharmacists. Neonatal ICU (NICU) services were also expanded. Separated from the adult pharmacy, St. David’s North has a dedicated NICU/pediatric pharmacy with a cleanroom for the preparation of IV medications and total parenteral nutrition. Although getting the dose right is a concern for any patient, when the patient weighs less than a few pounds, even the smallest error can have negative consequences. “A small difference in dosing can make a huge difference to a small pediatric or neonatal patient,” Mr. Pendley explained. To improve patient safety, both IV compounding rooms use the Dose Edge (Baxter) scanning and barcode system, which helps the pharmacists ensure the correct product is selected. It gives instructions for mixing and produces a picture of every step of the compounding process. “We not only found an added safety factor, we found a way to better document the entire process,” he said. “Everyone is aware of how barcoding and scanning is used to administer medications in hospitals, but according to an ISMP [Institute for Safe Medication Practices] Medication Safety Alert!, more hospitals should consider this type of technology in the preparation of IV products,” Mr. Pendley said. Only 6% to 7% of hospital pharmacies

Top photo: NICU beds await their little lit patients outside the antepartum unit. Bottom photo: h St. David’s d North h Austin Medical d l Center opened d a Children’s h ld Hospitall within h the general hospital with its own separate services, including a radiation department and pharmacy.

use any type of scanning and barcoding technology during the preparation of IV products, yet studies show that many errors are made during IV compounding ((ISMP Medication Safety Alert! Jan. 15, 2015). One study that looked at the accuracy of the preparation of smalland large-volume injectables, chemotherapy solutions and parenteral nutrition in five hospitals found an observed error rate of 9%, meaning that pharmacists made 145 errors for 1,679 doses prepared ((Am J Health-Syst Pharm 1997;54:904-912). Most of the errors were in dosing, and most were minor. But for every 100 errors made, two were

clinically significant, the study reported. “IV preparation is one of the most dangerous areas in the pharmacy where a mistake can have devastating consequences,” Mr. Pendley said. “Safe disposal of medications is just as important as dispensing,” he added. Between concerns about the diversion of controlled substances and local Environmental Protection Agency reservations about active pharmaceuticals winding up in the water supply, pharmacists have to be concerned about what happens with surplus and out-of-date products. St David’s HealthCare recently installed see ST DAVID’S, page 46

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46 Technology

Profiles in Pharmacy

Career Opportunities Education Financial & Legal Services Medical Equipment

For classiﬁed advertising, contact Craig Wilson

ST. DAVID’S continued from page 45

the Cactus Smart Sink, which securely captures dispensed unused pharmaceutical waste and renders it unrecoverable, nonretrievable and unusable, which helps reduce drug diversion and improve patient safety while also reducing the effect on the environment.

Smaller Beginnings When Jeanie Lively, RPh, pharmacy supervisor, started working at St. David’s North 16 years ago, the hospital had 120 beds. “If we had 85 patients, we thought we were busy,” she said and laughed. The hospital now has 332 beds. Today, the pharmacy has 43 fulltime employees; with the part-timers, 61 pharmacists and technicians handle the medication needs of between 300 and 400 inpatients and outpatients on any given day day, she said. said

narrowest spectrum possible to treat the organism determined by the culture?” She said the antibiotic stewardship program requires a good deal of their time, but not as much as it did before the pharmacists received Rx Vigilance Therapeutic Advisor (Telus Health), a decision support tool that provides ondemand access to up-to-date clinical and pharmaceutical information. Before the software update, they reviewed a stack of paper printouts to find information on cultures, international normalized ratios (INRs) for anticoagulants and potential interactions. This would take hours. Now, they receive alerts in real time and can make immediate adjustments. “This information is only available to the pharmacists. We evaluate the data and decide whether a clinical response is needed,” Dr. Getchell said. One of the latest deployments is the ED. St. David David’ss North had a trial period w with

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To improve patient safety, both the adult and the children’s IV compounding rooms use the Dose Edge (Baxter) scanning and barcoding systems

Education

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“When I started 12 years ago, the main pharmacy took care of everything,” Mr. Pendley added. “We’ve grown so much that we specialize now. We have NICU pharmacists, pediatric pharmacists, emergency room pharmacists and dedicated clinical pharmacists [in the main hospital].” Some of the best outcomes and lowest costs in the hospital come from the antibiotic stewardship and anticoagulant management program headed by Leslie Getchell, PharmD, clinical pharmacy coordinator. Dr. Getchell and another colleague provide clinical pharmacy services seven days a week. “We focus on any area where a physician, nurse or other pharmacist might want intervention, looking at patients charts and overuse, as well as adverse drug reactions,” she said. They also dose a lot of medications for physicians. “We are probably following about 35 patients a day on antibiotics,” she said. “Are they deescalating and using the

pharmacists in the t ED doing medication i i reconciliation ili i and d other services. After the intervention rate reached more than 90%, the ED pharmacist became a permanent fixture. “The trial was so successful, and the physicians and nurses were so happy with the services we were performing that we now have pharmacists in the ED,” Mr. Pendley said. “My personal goal is to try and get pharmacists on every unit and every floor of this hospital.” As physicians and nurses begin to understand their value, pharmacists are being deployed in more clinical areas of the hospital and not as tied to dispensing the product, he explained. “The traditional role of the pharmacist has been someone who dispenses medication,” he added. “But pharmacists have a tremendous knowledge about these medications that was just being under utilized.” —Marie Rosenthal

BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kabiven and Perikabiven safely and effectively. See full prescribing information, including Boxed Warning, for Kabiven and Perikabiven available at www.KabivenUSA.com. KABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 PERIKABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 WARNING: DEATH IN PRETERM INFANTS See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. INDICATIONS AND USAGE Kabiven and Perikabiven are each indicated as a source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Kabiven and Perikabiven may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients. Limitation of Use: Not recommended for use in pediatric patients < 2 years, including preterm infants, because the fixed content of the formulation does not meet nutritional requirements in this age group.

DOSAGE AND ADMINISTRATION

WARNINGS AND PRECAUTIONS

• Kabiven is for intravenous infusion only into a central vein • Perikabiven is for intravenous infusion into a central or peripheral vein • Recommended dosage depends on clinical status, body weight and nutritional requirements • Kabiven adult dosage: 19 to 38 mL/kg/day (0.63 to 1.26 g/kg/day of amino acids, 1.85 to 3.71 g/kg/day of dextrose, 0.74 to 1.48 g/kg/day of lipid) • The maximum infusion rate for Kabiven is 2.6 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.1 g/kg/hour of lipid) • Perikabiven adult dosage: 27 to 40 mL/kg/day (0.64 to 0.94 g/kg/day of amino acids, 1.83 to 2.71 g/kg/day of dextrose, 0.95 to 1.4 g/kg/day of lipid) • The maximum infusion rate for Perikabiven is 3.7 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.13 g/kg/hour lipid) • The recommended infusion period is 12 to 24 hours

• Hypersensitivity reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur • Infection, fat overload, hyperglycemia and refeeding complications: Monitor for signs and symptoms; monitor laboratory parameters

DOSAGE FORMS AND STRENGTHS • Kabiven and Perikabiven are sterile, hypertonic emulsions in a three-chamber container. The individual chambers contain one of the following: amino acids and electrolytes, dextrose, or lipid injectable emulsion, respectively • Kabiven is available in four sizes 2566 mL, 2053 mL, 1540 mL and 1026 mL • Perikabiven is available in three sizes 2400 mL, 1920 mL and 1440 mL CONTRAINDICATIONS • Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients • Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1000 mg/dL • Inborn errors of amino acid metabolism • Cardiopulmonary instability • Hemophagocytic syndrome

ADVERSE REACTIONS The most common adverse reactions to Kabiven (>3%) are nausea, pyrexia, hypertension, vomiting, decreased hemoglobin, decreased total protein, hypokalemia, decreased potassium and increased gamma glutamyltransferase. The most common adverse reactions to Perikabiven (> 3%) are hyperglycemia, hypokalemia, pyrexia and increased blood triglycerides. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coumarin and coumarin derivatives, including warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters USE IN SPECIFIC POPULATIONS Renal Impairment: Patients on hemodialysis or continuous renal replacement therapy may require additional supplementation to meet nutritional requirements. If required, adjust the volume of Kabiven or Perikabiven administered based on serum electrolyte levels and ﬂuid balance.

Si plify Now available Kabiven® and Perikabiven® Fresenius Kabi’s three-chamber bags for parenteral nutrition contain: • Amino Acids and Electrolytes • Dextrose • Lipids (Intralipid® 20% IV Fat Emulsion) www.KabivenUSA.com. To order, call 1-888-386-1300. Kabiven and Perikabiven three-chamber bags must be activated prior to infusion. For activation instructions see DIRECTIONS FOR ACTIVATING THE BAG in the prescribing information available at www.KabivenUSA.com. Neither Kabiven nor Perikabiven is recommended for use in pediatric patients < 2 years, including preterm infants because the ﬁxed content of the formulations do not meet the nutritional requirements in this age group. WARNING: DEATH IN PRETERM INFANTS

See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature. • Autopsy ﬁndings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients. Monitor patient closely for signs and symptoms of infection, hypertriglyceridemia, hyperglycemia and refeeding complications. Monitor laboratory parameters for alterations in electrolytes, liver and renal impairment, ﬂuid status and coagulation parameters. Adjust rate and dose of Kabiven and Perikabiven according to clinical status. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary of Prescribing Information, including Boxed Warning, for Kabiven and Perikabiven on the following page.

Brought to You by

REPORT Kcentra for Urgent Warfarin Reversal: Practical Considerations for Implementation Faculty Leah Hatfield, PharmD

Matthew Korobey, PharmD, BCPS

Lead Clinical Pharmacist Specialist Emergency Medicine University of North Carolina Hospitals and Clinics Chapel Hill, North Carolina

Education Coordinator Critical Care Clinical Care Specialist Mercy Hospital St. Louis, Missouri

Warfarin Anticoagulation and Risk for Bleeding

ong-term anticoagulation therapy is indicated for a wide variety of medical conditions including atrial fibrillation (AF) and thromboembolism.1,2 Currently available therapeutic agents are associated with a risk for bleeding that may require urgent reversal of anticoagulation with the goal of avoiding catastrophic outcomes.3 Fresh frozen plasma (FFP), thawed plasma, or factor concentrates are commonly used for urgent reversal of warfarin anticoagulation therapy. Factors II, VII, IX, and X, as well as antithrombotic proteins C and S, are all important in the effective emergency reversal of warfarin-induced bleeding.4,5 This monograph provides a brief overview of warfarin anticoagulation therapy and reviews practical considerations for implementing Kcentra, the first and only FDA-approved nonactivated 4-factor (4F) prothrombin complex concentrate (PCC) for urgent warfarin reversal, through the experience of clinical pharmacists at major medical institutions.

Arterial and venous thromboembolic events, including stroke and myocardial infarction, are leading causes of morbidity and mortality in the United States.6 Oral anticoagulants are especially critical in the prevention or recurrence of thromboembolic events among highrisk patients, including those with AF, venous thromboembolism, and mechanical heart valves.1 AF represents the most common indication for long-term oral anticoagulation, comprising roughly 40% of all patients requiring anticoagulation.7 Compared with their counterparts, patients with AF have a 5-fold increased risk for stroke, and oral anticoagulants reduce this risk by up to two-thirds.8,9 Vitamin K antagonists (VKAs), such as warfarin, have been the mainstay of oral anticoagulation therapy

Please see important safety information for Kcentra 速, Prothrombin Complex Concentrate (Human), on page 8, black box warning on page 2, and attached full prescribing information. Supported by

REPORT WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thrombo embolic events. Potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding. • Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. • Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. (5.2)

for many decades.10 They act by antagonizing the vitamin K-dependent γ-carboxylation of clotting factors II, VII, IX, X, which in turn block the extrinsic coagulation pathway. Warfarin also blocks γ-carboxylation of the antithrombotic proteins C and S, which serve to inhibit the function of factors V and VII in the coagulation cascade. Although warfarin is effective at reducing the risk for thrombosis, it has several drawbacks, including a narrow therapeutic index, slow onset and offset of action, interindividual differences in its metabolism, and numerous interactions with other drugs and dietary components, all of which complicate its clinical use.10-13 The most common complication of warfarin therapy is bleeding. In a study that included a cohort of more than 6,000 patients receiving warfarin therapy, the rate of major bleeding, including intracranial and gastrointestinal (GI) bleeding, was 3.6% per year (Table 1), with the risk for life-threatening bleeding occurring in 1.9% of patients per year and the risk for minor bleeding occurring in 16.4% of patients per year.3 In addition to the morbidity and mortality associated with these events, warfarin-related bleeding is linked to significant economic burden.14

Table 1. Annual Rates of Bleeding in a Large Clinical Trial of Patients Treated With Warfarin Warfarin (N=6,022) n

Life-threatening bleeding

218

1.85

Major bleeding

421

3.57

Gastrointestinal

148

1.25

Intracranial

0.76

1,931

16.37

Minor bleeding Adapted from reference 3.

Due to the limitations of warfarin therapy, scientists have concentrated efforts on developing novel oral anticoagulant drugs with improved safety and efficacy profiles.15 Although clinical studies of these agents have yielded promising data and have resulted in approval of their use in the clinical setting,15-17 longterm data are still required to determine their overall utility relative to warfarin. Furthermore, these therapies lack specific reversal agents, are costly, and may be unsuitable for many patients (eg, those with significant renal or hepatic impairment18 ); thus, the clinical use of warfarin is likely to continue for a significant number of patients for the foreseeable future.

Reversal of Anticoagulation: An Overview Because warfarin-related bleeding can result in significant morbidity and mortality, urgent and emergent reversal of anticoagulation is indicated in a variety of settings.19,20 Generally, warfarin reversal should be performed for severe or life-threatening bleeding in the brain, GI tract, deep muscles, retro-ocular region, joint spaces, or for any bleeding resulting in clinically significant changes in blood pressure or oxygen delivery to end organs that cannot be otherwise addressed by volume resuscitation and temporary use of blood transfusions.21 Furthermore, reversal of anticoagulation may be indicated for patients presenting with an urgent or emergent need for a surgical procedure or other invasive therapeutic intervention and for patients presenting with clinically significant trauma. Although experts agree that potentially life-threatening bleeding and bleeding associated with a high morbidity rate (eg, intracranial bleeding, major GI bleeding) require rapid warfarin reversal,22 other indications (eg, minor GI bleeding) require a consideration of the risk for thrombosis versus the adverse effects (AEs) of ongoing bleeding. The treatment strategy for warfarin reversal varies according to the acuity and severity of bleeding and the need for any invasive procedures.10,23 For example, minor and self-limiting bleeding might not require therapy, warfarin dose reduction, or temporary cessation of warfarin therapy alone. By contrast, minor persistent bleeding might require interruption of warfarin therapy combined with oral or IV use of vitamin K, whose onset of action typically requires 24 hours. Moderate or major bleeding, however, requires more rapid reversal of anticoagulation. There are several options for warfarin reversal in patients with moderate or major bleeding or for those patients receiving

REPORT warfarin who require emergent invasive procedures.24 FFP contains physiologic concentrations of all the coagulation factors present in blood and can therefore reverse the anticoagulation effect of warfarin. It should be noted that FFP is associated with several logistic drawbacks and AEs that limit its convenience, efficacy, and safety. For example, the practical time to effect of FFP is hampered by the need for ABO typing and product thawing, transport from the local blood bank, and the long infusion time. Furthermore, the volume of the FFP transfusion can be problematic in patients with cardiopulmonary compromise and can result in transfusion-associated circulatory overload and congestive heart failure. Finally, as with any blood product, FFP carries a risk for allergic and anaphylactic reactions as well as for transfusion-related lung injury (TRALI).24 Other options for warfarin reversal include recombinant factor VIIa and PCCs, which are formulated with 3 (II, IX, and X) or 4 factors (II, VII, IX, and X).22 These agents can be prepared more quickly and in a smaller volume than FFP, and also can be administered more rapidly. However, the FDA has only approved one of these agents for the reversal of warfarin anticoagulation associated with acute bleeding: the nonactivated 4F-PCC, Kcentra. Because vitamin K requires about 24 hours for maximum clinical effect, its use alone is insufficient for the rapid reversal of anticoagulation. Vitamin K is typically coadministered with FFP or PCCs to achieve durable reversal of warfarin anticoagulation. This step is important, as the half-life of clotting factors contained within FFP and PCC is relatively short and vitamin K administration will allow the endogenous synthesis of vitamin K-dependent clotting factors to begin.19,22,25

Improving Efficiency and Safety With Kcentra Commonly prescribed agents may not provide a complete reversal. Or, they may increase the risk for AEs. Another product was needed to address these clinical treatment gaps. Kcentra is a nonactivated 4F-PCC that contains the vitamin K-dependent factors II (prothrombin), VII, IX, and X, as well as the antithrombotic proteins C and S (Figure 1).26,27 This agent helps to restore blood coagulation by replenishing depleted levels of clotting factors resulting from warfarin therapy. In April 2013, Kcentra became the first nonactivated 4F-PCC to be approved by the FDA for urgent reversal of acquired coagulation factor deficiency induced by VKA therapy, such as warfarin, in adult patients with acute major bleeding. In December 2013, Kcentra received an expanded indication to include

urgent reversal of acquired coagulation factor deficiency induced by VKA therapy (eg, warfarin) in patients requiring an urgent surgical or invasive procedure. The FDA granted Orphan Drug Designation for Kcentra for these indications. Although only recently approved for use in the United States, Kcentra has been clinically used for more than 15 years as Beriplex® outside the United States.28

Reconstitution and Dosing Kcentra is available in single-use vials of 500 units (for use with 20-mL vial of sterile water for injection) and 1,000 units (for use with 40-mL vial of sterile water for injection).26 Before reconstitution, Kcentra can be stored at temperatures between 2°C and 25°C (36°F-77°F), including room temperature, and is stable for 36 months, up to the expiration date on the carton and vial labels.26 For reconstitution, addition of a sterile diluent to the Kcentra vial is accomplished with the Mix2Vial® filter transfer set.26 Comprehensive instructions for reconstitution along with illustrations are included in the package insert. The contents of multiple vials may be pooled, but a separate unused Mix2Vial® transfer set is required for each product vial. Kcentra dose is determined by the patient’s predose international normalized ratio (INR) and body weight, as detailed in the package insert (Table 2).26 Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded. Although the units of potency of all coagulation factors and proteins C and S are printed on the carton, dosing of Kcentra is standardized according to the factor IX units. Therefore, when calculating the Kcentra dose, it is important to check each vial for factor IX units because lots can vary in potency; the number of units for the other factors and antithrombotic proteins also is provided on the product carton (Figure 1). The factor IX content in each vial can range from 400 to 620 units for the 500 U kit and 800 to 1,240 units for the 1,000 U kit. When reconstituted, the final concentration of drug product in factor IX units will range from 20 to 31 units/mL.26 Kcentra should be used within 4 hours after reconstitution and should be administered at room temperature by IV infusion at 0.12 mL/kg per minute (~3 units/kg/min) up to a maximum rate of 8.4 mL per minute. 26 It should not be combined with other medicinal products, and therefore, should be administered through a dedicated IV line. 26 Kcentra is for single IV use; repeat dosing is not supported by clinical data

Figure 1. Approved Kcentra vial sizes.

REPORT and is not recommended. Because the clotting factors contained in Kcentra have a relatively short half-life, coadministration of vitamin K is necessary to maintain factor levels once the effects of Kcentra have diminished26 and should be administered through a separate infusion line.

Safety Patients receiving warfarin have underlying disease states that predispose them to thromboembolic events.26 Fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance of Kcentra. For these reasons, Kcentra prescribing information includes a boxed warning stating that the potential benefits of reversing VKA should be weighed against the risk for thromboembolic events, especially in patients with a history of such events. The safety and efficacy of Kcentra was investigated in several pivotal trials. In a Phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients who required urgent reversal of warfarin therapy because of acute major bleeding were randomized to Kcentra (n=98) or plasma (n=104).29 Effective hemostasis was achieved in 72.4% of patients receiving Kcentra compared with 65.4% of those receiving plasma (P=0.0045; 4F-PCC noninferior to plasma).29 Rapid INR reduction was achieved in 62.2% of patients receiving Kcentra versus 9.6% receiving plasma (P<0.0001), and measured coagulation factors were higher in the Kcentra group than in the plasma group (Figure 2).26,29 Both groups exhibited a similar AE profile.29 Additionally, the safety and efficacy of Kcentra in patients requiring warfarin reversal due to their need for an urgent surgery or invasive procedure was investigated in a Phase IIIb, open-label, noninferiority trial.30 Patients were randomized to Kcentra (n=87) or plasma (n=81). The study demonstrated both noninferiority and superiority of Kcentra on both its primary end points. Effective hemostasis was achieved in 90% of patients receiving Kcentra compared with 75% of patients

Table 2. Kcentra Dosing Pretreatment INR

2–<4

4–6

Dosea of Kcentra (unitsb of factor IX) / body weight (kg)

Maximum dosec (units of factor IX)

Not to exceed 2,500

Not to exceed 3,500

Not to exceed 5,000

INR, international normalized ratio a

Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20 to 31 factor IX units/mL after reconstitution. Nominal potency is 500 or 1,000 units per vial, approximately 25 units/mL after reconstitution.

International Units

Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

Based on prescribing information for Kcentra.

receiving plasma (P= 0.0142).30 Rapid INR reduction was achieved in 55% of patients receiving Kcentra versus 10% of those receiving plasma (P<0.001).30 Relative to the plasma group, measured coagulation factors were significantly higher in the Kcentra group.30 A posthoc analysis revealed no significant differences in the number of patients who experienced treatment-related AEs.30

Kcentra Implementation: Experience From Several Institutions Challenges are common whenever a new medication is adopted within a hospital formulary system, particularly when the medication is used for emergent indications. The following discussion reviews the experience of pharmacists from major medical institutions and their strategies for successfully adopting Kcentra for patients who require urgent reversal of warfarin therapy.

University of North Carolina Hospitals and Clinics (Chapel Hill, North Carolina) Leah Hatfield, PharmD, BCPS, is the lead clinical pharmacist specialist for emergency medicine for the University of North Carolina (UNC) Hospitals and Clinics. She is responsible for the clinical care of patients presenting to the emergency department (ED) and supervises the pharmacy and technician staff caring for these patients. Dr. Hatfield also oversees development and implementation of clinical protocols and drug use within the ED.

Implementation Dr. Hatfield noted the importance of developing institutional procedures for warfarin reversal and product selection. “We developed a formal emergent anticoagulation reversal guideline that we have been using for just over a year, and that guideline delineates the steps for emergent warfarin reversal, so it is stratified based on the patient’s INR at presentation and their risk for existence of bleeding events,” she said. Kcentra was added to the UNC formulary in August 2013 for use in emergent reversal. “We have an exceptionally large population of patients who are anticoagulated, both those taking warfarin and also those taking the novel oral anticoagulants. We felt it very necessary to get Kcentra added to the formulary and develop this guideline for emergent reversal for all of our warfarin patients,” she said. Advantages Dr. Hatfield outlined the benefits of using Kcentra for warfarin reversal and elaborated on the need for adding it to the formulary. “At our facility, we have the most exposure to 2 different agents: a 3F-PCC and Kcentra, which is a 4F-PCC. Both carry a risk for thromboembolic events. Currently, there are no established scientific literature or head-to-head trials to state that one would be more or less safe than the other. Recombinant factor VII, which is an older product, not only carries the warnings in its labeling but clinically in practice has been known to present a definitive risk for thromboembolic events. It is also significantly more expensive for a treatment course, frequently requires repeat dosing, and there is minimal established data on its use in reversing anticoagulation.” She continued, “Kcentra is somewhat ideal in that it hits all

REPORT factor components—II, VII, IX and X—and also includes antithrombotic proteins C and S. That gives it at least an anecdotal and theoretical clinical advantage, if not yet an evidence-based advantage over other factor products. Therefore, our clinical deduction is that Kcentra may be a more appropriate reversal agent than the 3F-PCC.” Reduced risk for fluid overload represents an additional advantage. “As far as other products, such as FFP that we would use for reversal, one of the reasons that we prefer Kcentra is the reduced volume. FFP has somewhat fallen out of favor due to the volume load that it presents for patients, especially patients with intracranial bleeding or cardiovascular compromise due to the risk for TRALI,” said Dr. Hatfield. Lower volume also confers a time-to-clinical-effect advantage. “It is quite a bit more rapid in onset than some of our other agents; so you can give bolus infusion and be relatively confident that you have reversed the patient adequately. Alternative therapies such as vitamin K or FFP are going to take hours to have that effect.” Additionally, Dr. Hatfield cited dosing simplification as another advantage of Kcentra. Specifically, Kcentra requires only single-dose administration. “An additional major advantage of Kcentra is that it is a single-dose reversal product, whereas some of the other factor agents occasionally require repeat doses for refractory bleeding,” she said. Dr. Hatfield’s facility is a Level 1 adult and pediatric trauma center, thus considerations for life-threatening bleeding events are paramount. “For severe or life-threatening bleeding events in patients taking warfarin, our first-line product is a 4-factor PCC,” she said. “Kcentra is our first-line reversal agent at this point for life-threatening bleeding events, such as intracranial bleeding, life-threatening GI bleeding, and traumatic bleeding in patients on warfarin.”

Percentage of subjects

80% 70% 62.2% 60% 50% 40% 30% 20% 9.6%

10% 0 Kcentra + Vitamin K n=98

Plasma + Vitamin K n=104

Figure 2. Proportion of subjects experiencing a reduction of INR (≤1.3 at 30 minutes after end of infusion). INR, international normalized ratio Kcentra – plasma (%) [95% CI] = 52.6 [39.4, 65.9] (prespecified superiority margin > 0). Adapted from prescribing information for Kcentra.

Safety is always a concern for clinicians. Kcentra presents a comparable safety profile compared with plasma. “From a safety standpoint, FFP and vitamin K are certainly relatively safe in the right context. With Kcentra, we’re assuming that we are getting a more complete reversal of the warfarin. The singular concern would be the potential for thromboembolic events, but other factor concentrates or older agents such as recombinant factor VII carry the same risks. There is a large body of evidence with use of 4F-PCC abroad that supports available safety data. Based on the evidence we have to date, 4F-PCC appears in line with its clinical comparators, and carries less risk for hemodynamic compromise than FFP.”

Preparation and Administration Because the indications for Kcentra are often urgent, reducing the time from ordering to administration is important for hospital pharmacies. “It generally takes multiple vials to make one dose for a patient, and so even with a fairly skilled individual it can take 15 to 20 minutes to prepare a dose,” she said. “At this point, it is not something that can be easily put into an automated dispensing machine in the emergency department; it has to come from the central inpatient pharmacy or be prepared by the ED pharmacist.” Dr. Hatfield and her team have developed strategies to overcome this challenge. “First, our protocol has preset parameters for dosing,” she said. “It tells the ordering provider the appropriate dose based on the patient’s weight and background clinical information. Second, it is built into an order set in our CPOE [computerized prescriber order entry] system so it is automatically a STAT product, which triggers the staff in the central pharmacy to know that it is needed urgently. We’ve also moved the physical location of the drug to be right next to the preparation area. These steps helped us reduce the preparation and delivery time from about 60 minutes to less than 20 minutes.” Dr. Hatfield described strategies that her institution uses to facilitate administration of Kcentra. “We have smart infusion pumps, with a prebuilt entry that includes guardrails and safety parameters for dosing and infusion rates,” she said. “For example, all patients that weigh over 70 kg will have their pumps automatically set at the maximum infusion rate of 8.4 mL per minute. This allows us to deliver many of our doses in 10 to 15 minutes. Our technicians reconstitute each vial individually using the Mix2Vial® filter transfer set that is provided by the manufacturer. We reconstitute all the vials together, and then they’re drawn up and placed in an empty Vacutainer sterile bag that is hand-delivered to the patient’s bedside.” Provider Education Dr. Hatfield stressed the importance of training providers about the product—what it is, what it does, and how to use it appropriately. This education is critical to achieve effective warfarin reversal. Because preparing the vial may be fairly complex without proper information, successful implementation will likely require extensive training and guideline development. “We arranged a number of very aggressive in-services for many of our service lines, including hematology, emergency medicine, and neurocritical care staff, along with attendings in our other intensive care units, and all inpatient pharmacists,” she said. “If you don’t have smart infusion pumps available to assist with appropriate mechanisms for administering the product, nursing in-services and education are essential.” Additionally, Dr. 5

REPORT Hatfield explained, “We devised a comprehensive reversal protocol and sent it through all of our executive hospital committees, which had the side benefit of providing an opportunity to educate them on the product and how to appropriately use it. We also implemented formulary restrictions to ensure appropriately skilled providers were evaluating the patients and making prudent treatment decisions.” Dr. Hatfield has found customer support helpful for learning preparation and administration. “Their customer service line [Kcentra Hotline] is exceptionally well staffed. I have experienced fast responses and solid clinical information from experienced personnel, without long waits for return calls or emails,” she said. “When I speak to my counterparts at other institutions, I tell them that I’m very much in favor of adopting Kcentra because, in my personal opinion, it is the easiest, safest, and quickest product that we have available for life-threatening, emergent warfarin anticoagulation reversal at this time. It is also currently the only FDA-approved product for urgent reversal of life-threatening warfarin-associated bleeding.”

Mercy Hospital (St. Louis, Missouri) Matthew Korobey, PharmD, is the adult critical care clinical specialist at Mercy Hospital. Mercy St. Louis is an approximately 1,000-bed community-affiliated teaching hospital. Dr. Korobey oversees Kcentra usage at Mercy Hospital. “Any time an order is placed for Kcentra, we have surveillance software that will register its ordering and alert me. I review the patient’s chart to make sure that its use is appropriate, that it is a lifethreatening or an urgent need for warfarin reversal, and that the vitamin K is administered. This is a real-time ‘quality assurance’ strategy,” he said.

Provider Education Dr. Korobey believes it is imperative to inform clinicians of the benefits of Kcentra. “It’s helpful to tell clinicians that, in contrast to FFP, in which there are no truly systematic approaches to dosing and utilization, Kcentra has concrete, easy-to-use recommendations based on the patient’s INR and body weight, resulting in more accurate dosing and better reversal,” he said. Additionally, Dr. Korobey found that many clinicians were previously unaware of the large body of clinical experience with Kcentra. “I found that the clinical use of Kcentra is not new,” he said. “It has been used for quite some time in Europe [as Beriplex], and there is an extensive amount of information on its use. This information seems to provide the clinicians with considerable comfort when they are considering its use.” Dr. Korobey also noted the need for comprehensive education with respect to concurrent administration of vitamin K with Kcentra. “The biggest issue I run into is the hesitance to use vitamin K in combination with the product, specifically for a procedural reversal,” he said. “Providing clinicians with real-world examples of what happens—rebound anticoagulation and bleeding complications—if you don’t take the proper steps has been very effective. I think explaining that the management strategy should be exactly the same as with FFP. The effect of warfarin will persist unless you synthesize the vitamin K-dependent clotting factors. In reality, vitamin K is not an acute reversal agent; instead, it ensures that the reversal stays and is constant.” Kcentra includes a Mix2Vial® filter transfer set that is used to facilitate addition of the diluent to the Kcentra vial for 6

reconstitution. This is an important feature that simplifies an otherwise complex process for clinicians new to the product. “The Mix2Vial® system was new to us, but it has been an easy thing to teach,” said Dr. Korobey. “Do one-on-one teaching whenever possible, especially for pharmacists in the ED, because a lot of times, Kcentra will be reconstituted there. It looks intimidating, but it is an ingenious and simple system. I had a student today mix it on her first try with no problem whatsoever.” Additionally, dosing has not been a problem with Kcentra. “We developed a policy that allows us to minimize waste, but this is standard practice for all of our factor replacement products. It wasn’t necessarily a big headache,” said Dr. Korobey. It is important to review the dosing of Kcentra according to factor IX content with pharmacy staff. “Every vial or every lot contains different amounts of factor IX units. Our order, in our medical record would be just 25 units/kg or 35 units/kg, and it doesn’t at all account for the various concentrations in the vials,” he said. “So, teaching everyone where to locate the actual factor IX units on the vial is important.” The ability to store Kcentra at room temperature is a significant advantage. Dr. Korobey remarked, “The storage is really nice; I am very happy that Kcentra is a dry powder and that it doesn’t have to be refrigerated. That, combined with the 3-year shelf life, means that we can keep a much larger stock, which is an advantage when patients require multiple vials for their dose.”

Customer Support and Cost Benefits Dr. Korobey values the customer support resources as a strategy to overcome any challenges when adopting Kcentra within a formulary. “The Kcentra reps have always been more than willing to give assistance. When we first procured Kcentra, I talked to the rep about some hesitance in the new mixing process, and he sent over mock mixing kits so my staff could have hands-on training. They have been very helpful with anything I have requested from them.” Moreover, the Centers for Medicare & Medicaid Services (CMS) new technology add-on payment (NTAP) policy supports timely access to innovative therapies for Medicare beneficiaries in the inpatient hospital setting. To be eligible for an NTAP, the new product must provide a substantial clinical improvement over existing therapies. CMS announced that it reimburses hospitals up to $1,587.50, for cases involving Kcentra that exceed the Medicare Severity Diagnosis-Related Groups payment amount.31 “This is very helpful from a cost perspective,” Dr. Korobey said. “We have used the NTAP reimbursement code without problems. I use this as a selling point for my providers when they want information. I say ‘why would I choose Kcentra over FFP?’ The government looks at this as a promising enough product that it will reimburse the institution additionally to encourage its use. There are not many products out there we can say that about. I think it really speaks to the faith in this product.” Kcentra provides other notable, but less immediately visible, cost benefits. “I think a lot of the benefit you see from using FFP comes from soft cost reduction,” said Dr. Korobey. “You are preventing complications and it is really hard to quantify those, but I would suggest to anyone who is having trouble bringing the product on the formulary to look at the rates of TRALI associated with FFP. Look at the costs associated with those, and then translate that information to dollars saved

REPORT in preventing those complications.” It is important to convey these potential cost savings to pharmacy and hospital administration. “We fought hard to bring it [Kcentra] on board as part of our formulary. We favor it over FFP, not necessarily because of cost, but because of ease of administration, the predictable nature of the INR reduction, and the reduced volume and exposure to blood products.”

Conclusion Indications for long-term anticoagulation with warfarin are common, but the safety of warfarin anticoagulation is limited by the rate of and risk for bleeding. Rapid reversal of warfarin

anticoagulation is needed for patients with acute major bleeding, as well as for patients who require an urgent surgery or invasive procedure. Kcentra is the first and only FDA-approved nonactivated 4F-PCC for urgent reversal of acquired coagulation factor deficiency induced by VKA therapy (eg, warfarin). Compared with plasma, Kcentra has a faster time to clinical effect and a comparable safety profile. According to pharmacists experienced with Kcentra, successful implementation can be achieved with appropriate training, institutional guideline development, and monitoring to ensure safe and appropriate use.

References 1. Fuster V, Rydén LE, Cannom DS, et al. Guidelines for the management of patients with atrial fibrillation – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for Management of Patients with Atrial Fibrillation). J Am Coll Cardiol. 2006;48(4):854-906.

16. Xarelto [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc.; 2014.

2. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2):527-539.

19. Baker RI, Coughlin PB, Gallus AS, et al. Warfarin Reversal Consensus Group. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181(9):492-497.

17. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc., 2014. 18. Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood. 2010;115(1):15-20.

3. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123(21):2363-2372.

20. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105(2):91-99.

4. Zareh M, Davis AJ, Henderson SO. Reversal of warfarin-induced hemorrhage in the emergency department. West J Emerg Med. 2011;12(4):386-392.

21. Vigué B. Bench-to-bedside review: optimizing emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice. Critical Care. 2009;13(2):209.

5. Lipe B, Ornstein DL. Deficiencies of natural anticoagulants, protein c, protein s, and antithrombin. Circulation. 2011;124(14):e365-e368.

22. Hanley JP. Warfarin reversal. J Clin Pathol. 2004;57(11):1132-1139.

6. Heron M. Deaths: leading causes for 2004. Natl Vital Stat Rep. 2011; 59(5):1-95.

23. Ageno W, Garcia D, Aguilar MI, et al. Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, part 2: treatment. Am J Hematol. 2009;84(9):584-588.

7. Kirley K, Qato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes. 2012;5(5):615-621.

24. Tran HA, Chunilal SD, Harper PL, et al. Australasian Society of Thrombosis and Haemostasis (ASTH). An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198(4):198-199.

8. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-988.

25. Matthew AE, Kumar A. Reversal of anticoagulation. ACEP Now. http://www.acepnow.com/article/reversal-anticoagulation/. Accessed March 18, 2015.

9. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.

26. KCENTRA [prescribing information]. King of Prussia, PA: CSL Behring, 2014.

10. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based guidelines. Chest. 2012;141(2 suppl):e44s-e88s. 11. Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and γ-carboxyglutamic acid-deficient prothrombins. J Biol Chem. 1985;260(1):279-285. 12. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation Guide to warfarin therapy. Circulation. 2003;107(12):1692-1711.

27. [No authors listed] Kcentra: a 4-factor prothrombin complex concentrate for reversal of warfarin anticoagulation. Med Lett Drugs Ther. 2013;55(1420):53-54. 28. Kcentra, from CSL Behring, receives FDA approval for use in warfarin reversal in patients undergoing surgery [press release]. King of Prussia, PA; December 13, 2013. 29. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243.

14. Kim MM, Metlay J, Cohen A, et al. Hospitalization costs associated with warfarin-related bleeding events among older community-dwelling adults. Pharmacoepidemiol Drug Saf. 2010;19(7):731-736.

30. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomized trial. The Lancet. 2015. [Epub ahead of print]. doi: http://dx.doi.org/10.1016/S01406736(14)61685-8.

15. Hull RD, Gersh MH. The current landscape of treatment options for venous thromboembolism: a focus on novel oral anticoagulants. Curr Med Res Opin. 2015;31(2):197-210.

31. Department of Health and Human Services. Centers for Medicare and Medicaid Services. Rules and Regulations. Federal Register. 2013;78(160):50495-51040.

13. Coumadin [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2011.

REPORT Important Safety Information Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months. Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with disseminated intravascular coagulation. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT). Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment. In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis. Kcentra is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed. Please see full prescribing information for Kcentra.

Disclosures: Dr. Hatfield has nothing to disclose. Dr. Korobey reported that he has served as a consultant for CSL Behring.

May 2015

Kcentra®, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. Kcentra is for intravenous use only. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months.

SR144

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, CSL Behring, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.